Rapidly Progressive Pericardial Metastasis in SMARCA4-Deficient Non–Small Cell Lung Cancer: Implicating the SWI/SNF-YAP-EMT Axis

Rapidly Progressive Pericardial Metastasis in SMARCA4-Deficient Non–Small Cell Lung Cancer: Implicating the SWI/SNF-YAP-EMT Axis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Rapidly Progressive Pericardial Metastasis in SMARCA4-Deficient Non–Small Cell Lung Cancer: Implicating the SWI/SNF-YAP-EMT Axis Shanshan Zhao, Pengcheng Tan, Yuejue Mu, Song Tan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8666173/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background SMARCA4-deficient non–small cell lung cancer (SMARCA4-dNSCLC) is a rare and aggressive subtype with rapid progression and poor prognosis. Patterns of pericardial invasion and their biological mechanisms remain insufficiently characterized. Case Presentation A 46-year-old man presented with a mediastinal mass that enlarged from 4.9 cm to 7.1 cm over nine months. Despite relatively gradual enlargement of the primary lesion, the clinical course was abruptly dominated by diffuse pericardial involvement. Serial imaging demonstrated circumferential, infiltrative pericardial thickening with an armor-like configration, leading to restrictive cardiac physiology and fatal hemodynamic compromise. Cytological and immunohistochemical revealed malignant epithelial cells with TTF-1 (-), p40 (-), CK7 (+), and MOC31 (+), accompanied by markedly elevated proliferative index of Ki-67. Heterogeneous loss of SMARCA4/BRG1 confirmed the diagnosis of SMARCA4-dNSCLC. Conclusions This case illustrates a pericardial, non-linear progression pattern in SMARCA4-dNSCLC. Early recognition of SMARCA4 deficiency through SMARCA4/BRG1 immunohistochemistry is essential, as such aggressive kinetics may warrant early systemic evaluation. This case supports a hypothesis that SMARCA4 deficiency sensitizes cells to YAP-driven EMT program, while cardicac-derived mechanical strech provides a permissive microenvironment, synergistically contributing to the aggressive, armor-like pericardial thickening in this malignancy. Epigenetics & Genomics Oncology Translational Medicine SMARCA4 SWI/SNF chromatin remodeling YAP/TAZ SMARCA4-dNSCLC pericardial involvement Figures Figure 1 Figure 1 Figure 2 Figure 3 Figure 3 Introduction Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Patient prognosis and therapeutic responsiveness are strongly associated with specific genomic and epigenetic alterations. SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) has emerged as a distinct and clinically aggressive subtype, which is characterized by poor differentiation and dismal outcomes 1 . The SMARCA4 gene, located on chromosome 19p13.2, encodes the catalytic ATPase SMARCA4/BRG1, the core enzymatic subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex 2 . This complex plays a central role in regulating chromatin organization, transcription programs, DNA repair, and lineage maintenance 2 . Loss of SMARCA4 function, through genetic mutation, promoter methylation, or protein depletion, results in global transcriptional dysregulation, impairment of cell-cycle control, and enhanced cellular plasticity 3 . These alterations are implicated in the pathogenesis of highly aggressive malignancies, including thoracic sarcomatoid tumors, and thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). SMARCA4-dNSCLC is clinically characterized by early metastatic dissemination, a high proliferative index, and limited sensitivity to standard chemotherapy 4 . Emerging studies suggest that these tumors undergo metabolic reprogramming with increased reliance on oxidative phosphorylation 5 . While mediastinal and pleural involvement are frequently observed, abrupt pericardial infiltration has rarely been described, and the biological mechanisms underlying this apparent serosal tropism remain poorly understood 6 . Here, we present a case of SMARCA4-dNSCLC marked by rapid and diffuse pericardial involvement that became the dominant driver of clinical deterioration. This report provides insight into the aggressive and non-linear disease kinetics associated with SMARCA4 deficiency and underscores the importance of early molecular recognition in guiding diagnostic and therapeutic decision-making. Case Presentation A 46-year-old male with a 30-pack-year smoking history was incidentally found to have multiple bilateral pulmonary nodular opacities during a workup for a thoracic vertebral fracture in Feburary 2025 (Month 0.0). Chest computed tomography (CT) demonstrated a 4.6*3.3 cm pretracheal mass posterior to the superior vena cava (SVC), with multiple mediastinal lymphadenopathies. Initial recommendations include re-examination and close observation. By Month 1.5, the patient developed dyspnea and was treated for suspected pneumonia with intravenous antibiotics for two months at an outside institution. A lack of symptomatic relief and the emergence of hemoptysis promoted repeat chest CT at Month 3.4, showing progression of the mediastinal lesions. Initial percutaneous lung biopsy was nondiagnostic and complicated by significant hemorrhage. Endobronchial ultrasound-guided needle aspiration (EBUS-TBNA) was performed on Month 5.0 demenstrated malignant epithelial cells. Immunohistochemistry (IHC) analysis revealed heterogeneous loss of SMARCA4/BRG1 (absent in the majority of tumor cells), and a Ki-67 proliferation index of appropriate 40%. Tumor cells were CK7 (+), TTF-1 (-), Napsin A (-), CK5/6 (-), and preserved INI-1 expression, consistent with SMARCA4-dNSCLC. Genomic profiling revealed no actionable driver mutations. Percutaneous embolization of internal thoracic artery (Month 5.1) controlled refractory hemoptysis but was complicated by intraoperative atrial fibrilation, managed with lanatoside C. Thoracentesis (Month 5.2) revealed malignant plueral effusion. By Month 5.3, irregular atrial flutter and pericardial effusion emerged, confirmed by pericardial drainage (Month 5.4) as hemorrhagic and malignant. The patient and his family declined systemic chemotherapy and immunotherapy, receiving only palliative radiation therapy (30 Gy in 10 fractions, Month 5.4-6.0). Serial imaging from Month 6.2 to Month 7.0 demenstrated rapid mediastianl mass growth (7.1*6.0 cm) with the SVC and right upper lobe vascular involvement, increased bilateral pleural effusions, and progressive circumferential pericardial thickening. The longitudinal clinical course timeline and radiographic progression is illustrated in Fig. 1 . At presentation, the pericardium appeared thin and unremarkable on chest CT. By Month 6.2, CT imaging revealed newly developed circumferential pericardial thickening, measuring 14.62 mm. At final CT (Month 9), the pericardium had formed an armor-like encasement of the heart, with maximal thickness up to 33.58 mm (Fig. 1 B). And representative transthoracic echocardiographic images are illustrated in Fig. 1 C. By Month 8.5, echocardiography revealed persistent massive pericardial effusions and a new 2.2 *1.8 cm right upper lobe nodule. Laboratory evaluation indicated myocardial injury and systemic inflammation: WBC 23.3 × 10^9/L, hemoglobin 76 g/L, IL-6 758.77 pg/mL, troponin I 0.34–0.61 ng/mL, BNP 293.2 pg/mL, and D-dimer 2.28 mg/L. Pleural fliud cytology confirmed highly proliferative adenocarcinoma cells (MOC31 (+), Calretinin (-), TTF-1 (-), p40 (-), insulinoma-associated protein 1 (INSM1) (-), Napsin A (-), and Ki-67 ~ 90%) with heterogenous SMARCA4/BRG1 loss, consistent with aggressive SMARCA4-dNSCLC (Fig. 2 ). Despite supportive care, the patient died shortly after hospital discharge on Month 9.0. A detailed timeline of the clinical course is provided in Supplementary Table 1. Disscussion The biological behavior of SMARCA4-dNSCLC represents a state of extreme oncogenic fitness. This case uniquely captures the uninterrupted natural history of the disease over a nine-month course. The disease evolved from relatively modest mediastinal mass into diffuse, circumferential pericardial encasement, revealing a distinctly non-linear kinetics. Mechanistic considerations: the SMARCA4-YAP-EMT axis Unlike focal or hematogenous metastasis, which typically manifesting as pericardial effusion in pulmonary adenocarcinoma 7 , this patient developed an armor-like infiltrative thickening of the pericardium. The aggressive phenotype observed can be partially attributed to heterogeneous loss of SMARCA4/BRG1. As the catalytic core of the SWI/SNF chromatin-remodeling complex, SMARCA4 maintains epithelial lineage fidelity through epihgenetic constraint 8 . Spatially incomplete or subclonal SMARCA4 loss increases transcriptional plasticity, allowing tumor cell subsets to acquire invasive and mesothelial-interactive properties 9 . Such epigenetic instability provides a permissive substrate for adaptation to non-parenchymal microenvironments, including pericardial surfaces 10 . Mechanical signaling may further contributed to the unusual pericardial encasement observed in this case. The pericardium is a mechanically dynamic tissue, continuously exposed to cyclic stretch generated by cardiac motion 11 . Tumor cells infiltrating this environment are therefore subjected to persistent mechanical stress. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are central mediators of mechanical transduction 12 . Increased matrix stiffness or cytoskeletal tension from cyclic mechanical strain activate RhoA-ROCK signaling, promote F-actin polymerization, facilitating YAP/TAZ nuclear translocation by suppressing Hippo pathway and flattening the nucleus 13 . Nuclear YAP/TAZ then engage TEAD transcription factors to induce gene programs involved in epithelial-mesenchymal transition (EMT), a process by which epithelial tumor cells acquire invasive and migratory properties 14 , 15 . Loss of SMARCA4 alters this process at the chromatin level. Normally, SMARCA4-containing SWI/SNF complex restrains YAP/TAZ transcriptional output by maintaining a closed chromatin state at TEAD-bound enhancers and stabilizing epithelial lineage 16 . SMARCA4 deficiency increases chromatin accessibility at YAP/TAZ-responsive loci, facilitating the constitutive recruitment of the YAP/TAZ-TEAD transcriptional complex. As a result, mechanical signals, such as cardiac cyclic strech, which would normally elicit limited responses or transient transcriptional responses, instead trigger amplified and sustained YAP/TAZ-driven EMT programs and matrix metalloproteinase (MMP) expression 12 , 17 . The accumulation of pericardial effusion may further increase tissue stiffness, establishing a self-reinforcing mechanobiological feedback loop (Fig. 3 ). Within this mechanically constrained pericardial niche, SMARCA4-deficient subclones may therefore gain a competitive fitness advantage. This model provides a mechanistic explanation for the diffuse, armor-like pericardial expansion observed in this patient rather than focal nodular invasion. The resulting thickened, fibrotic remodeling and cardiac restriction became the dominant determinants of clinical deterioration and mortality. Further validation of this proposed mechanism will require spatially resolved transcriptomic analyses and biomechanically informed model systems. SMARCA4-dNSCLC versus SMARCA4-UT and potential therapeutic strategies Accurate distinction SMARCA4-dNSCLC and SMARCA4-UT is still a subject of debate. Unlike SMARCA4-UT, which typically demonstrates uniform SMARCA4 loss, rhabdoid morphology, and complete absence of epithelial differentiation, the present tumor retained adenocarcinoma morphology and expressed epithelial markers including CK7 and MOC31 6,18 . The heterogeneous SMARCA4/BRG1 loss supports a classification as SMARCA4-dNSCLC with loss of lineage-specific differentiation, rather than SMARCA4-UT 18 . And SMARCA4-dNSCLC is highly smoking-associated. This case underscores limitations of routine diagnostic workflows. Next-generation sequencing may fail to detect SMARCA4 alterations due to epigenetic silencing, or subclonal loss. Incorporation of SMARCA4immunohistochemistry into the initial diagnostic evaluation of high-grade thoracic tumors is therefore critical to avoid under-recognition of this aggressive subtype. Early recognition of SMARCA4-dNSCLC has direct prognostic and therapeutic implications, as SMARCA4-deficient tumor frequently exhibit rapid clinical deterioration that is poorly controlled by surgery and radiation 6 . Therapeutic options for SMARCA4-dNSCLC remain limited. Conventional platinum-based chemotherapy regimens offer modest efficacy, while immunetherapy outcomes are variable even in tumors with favorable fatures, such as heavy smoking history and high proliferative indices 19 – 21 . Preliminary data suggest that combining ICIs and chemotherapy with anlotinib may improve survival 19 , yet identifying biomarkers to predict both ICIs efficacy and immune-related adverce events remains a critical need 20 – 22 . Translational studies have identified multiple downstream consequences of SMARCA4 loss, including epigenetic reprogramming involving BRCA1 impairment, pRB-associated cell-cycle dysregulation, and MYC-dependent transcriptional dependency 23 , 24 . These insights have prompted preclinical exploration of epigenetic therapies. However, a standard of targeted approach has yet to be established for SMARCA4-deficient tumors. In this case, the pericardium acts as a mechanicalbiological niche favoring YAP/TAZ activation. SMARCA4 loss may sensitize tumor cells to these physical cues, enabling disproportionate invasive responses. This identifies a specific mechanobiological vulnerability worthy of further study. Conclusions This report describes a fatal phenotype of SMARCA4-dNSCLC in which rapid pericardial invasion dominated clinical deterioration. The presentation underscores the marked biological plasticity associated with SMARCA4 deficiency. Early recognition of SMARCA4-deficient tumors is therefore essential. The pericardium-centered disease course suggests that loss of SMARCA4 may relax epigenetic constraints on periardial involvement, highlighting a potential avenue for future translational investigation. Declarations Conflict of Interest There is no conflict of interest. Contributions of Authors S. Zhao contributed to conceiving the study, original manuscription writing, submission and clinical information collection. P. Tan and Y. Mu were involved in the management and follow-up of the patient. Song Tan provided funding. Ethics and Patient Consent Declaration This study was approved by the Ethics Committee of Yantai Hospital of Traditional Chinese Medicine (Approval No. 2025-KY-027). The kin of patient consents to the publication using the clinical information. The kin has signed a form of patient consent for this case report publication. Acknowledgement Thans to he Department of Pathology at Yantai Hospital of Traditional Chinese Medicine for their technical assistance with histological examinations. This study was funded by the Natural Science Foundation of Shandong Province, China (Grant No. ZR2022LZY013). The proposed mechanistic figure is created in biorender.com. While preparing this work, the author used Open AI for the purpose of language polishment and to enhance the readability of the text. The author formally reviewed the content for its accuracy. 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Cell 102:257–265. https://doi.org/10.1016/S0092-8674(00)00030-1 Romero OA, Setien F, John S, Gimenez-Xavier P, Gómez‐López G, Pisano D, Condom E, Villanueva A, Hager GL, Sanchez‐Cespedes M (2012) The tumour suppressor and chromatin‐remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 4:603–616. https://doi.org/10.1002/emmm.201200236 Additional Declarations The authors declare no competing interests. Supplementary Files supplementarytable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8666173","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":578551932,"identity":"563e6784-266c-4e48-8332-e7c73bef254b","order_by":0,"name":"Shanshan Zhao","email":"","orcid":"","institution":"Department of Oncology, Yantai Hospital of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Zhao","suffix":""},{"id":578552316,"identity":"27188f6f-a3cd-4f2f-96a5-550c03b53b34","order_by":1,"name":"Pengcheng Tan","email":"","orcid":"","institution":"Department of Oncology, 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09:07:19","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":88750,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/3f8d6d8c7f82faab7291149f.png"},{"id":100964294,"identity":"ffcc49c0-19f3-41f4-a5a1-864f8dc77821","added_by":"auto","created_at":"2026-01-23 09:07:19","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69713,"visible":true,"origin":"","legend":"","description":"","filename":"rs86661730structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/b798f9c520e9188242a6403f.xml"},{"id":101203406,"identity":"776f0a01-a851-4d89-8cfc-fb2c867f6850","added_by":"auto","created_at":"2026-01-27 09:39:34","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":76705,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/94dd8b4730ddff0d942f0bfb.html"},{"id":101203271,"identity":"576ffd6c-7ef7-408c-8d6b-1bc1d54a25eb","added_by":"auto","created_at":"2026-01-27 09:39:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":6596278,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal clinical and radiographic progression of the SMARCA4-dNSCLC.\u003c/strong\u003e (A) The timeline (Day 0-273) illustrates the transition from an incidental discovery to progressive systemic decline. Key milestones include: (Day 0) initial chest CT; (Day 150) diagnosis of SMARCA4 deficiency via EBUS; (Day 162-188) development of malignant pericardial effusion and cardiac abnormalities; and (Day 258-267) terminal clonal evolution marked by a rapid accelaration of the Ki-67 index from 40% to 90%, accompanied by persistent myocardial injury. (B) Serial contrast-enhanced chest computed tomography (CT) demonstrating progressive, circumferential pericardial thickening. The maximal pericardial thickness is indicated by white solid lines on representative axial images, illustrating the rapid infiltrative remodeling of the pericardium over time. (C) Representative transthoracic echocardiographic images showing progressive cardiac functional impairment, including abnormal ventricular wall motion and altered intracardiac flow patterns, consistent with restrictive cardiac physiology secondary to malignant pericardial involvement.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/a2e64184ab6517ee2be95a1a.png"},{"id":101001253,"identity":"016be253-4a20-4ffc-9f01-5170cbd187f2","added_by":"auto","created_at":"2026-01-23 16:35:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":6596278,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal clinical and radiographic progression of the SMARCA4-dNSCLC.\u003c/strong\u003e (A) The timeline (Day 0-273) illustrates the transition from an incidental discovery to progressive systemic decline. Key milestones include: (Day 0) initial chest CT; (Day 150) diagnosis of SMARCA4 deficiency via EBUS; (Day 162-188) development of malignant pericardial effusion and cardiac abnormalities; and (Day 258-267) terminal clonal evolution marked by a rapid accelaration of the Ki-67 index from 40% to 90%, accompanied by persistent myocardial injury. (B) Serial contrast-enhanced chest computed tomography (CT) demonstrating progressive, circumferential pericardial thickening. The maximal pericardial thickness is indicated by white solid lines on representative axial images, illustrating the rapid infiltrative remodeling of the pericardium over time. (C) Representative transthoracic echocardiographic images showing progressive cardiac functional impairment, including abnormal ventricular wall motion and altered intracardiac flow patterns, consistent with restrictive cardiac physiology secondary to malignant pericardial involvement.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/3f41dc372e6c40f7b443f055.png"},{"id":100964289,"identity":"f81478f4-756e-42e1-887c-540e9b894900","added_by":"auto","created_at":"2026-01-23 09:07:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12749809,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCytological and immunohistochemical characterization of malignant pleural effusion. \u003c/strong\u003e(A) Cytological examination of pleural fluid demonstrating malignant epithelial cells with adenocarcinoma morphology (HE staining).\u003cstrong\u003e \u003c/strong\u003e(B) SMARCA4/BRG1 immunohistochemistry showing heterogeneous loss of nuclear expression in tumor cells. (C-H) Immunohistochemical staining showing tumor cells positive for MOC31 and negative for TTF-1, p40, Napsin A, Calretinin, and INSM1, supporting epithelial origin and excluding mesothelial, squamous, and neuroendocrine differentiation.\u003cstrong\u003e \u003c/strong\u003e(I) Ki-67 immunostaining revealing a markedly elevated proliferative index (approximately 90%).\u003cstrong\u003e \u003c/strong\u003ePositive immunoreactivity is indicated by blue triangles, while negative staining is marked by green triangles. Scalbar, 100 µm.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/957c11ccdf7477b65db85aba.png"},{"id":101296627,"identity":"b8fa6530-2b8d-4853-9135-5ab4e1a55e43","added_by":"auto","created_at":"2026-01-28 09:17:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":599255,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed mechanobiological mechanism of pericardial encasement in SMARCA4-dNSCLC\u003c/strong\u003e. (i) Epigenetic dysregulation: SMARCA4/BRG1 deficiency disrupts SWI/SNF-mediated chromatin organization, leading to loss of epithelial lineage stability, increased transcriptional plasticity. (ii) YAP/TAZ activation and nuclear F-actin coupling: Loss of SMARCA4 impairs chromatin-mediated restraint of YAP/TAZ-TEAD-dependent transcription. Increased matrix stiffness or cytoskeletal tension from cyclic mechanical strain activate RhoA-ROCK signaling, promote F-actin polymerization, facilitating YAP/TAZ nuclear translocation by suppressing Hippo pathway and flattening the nucleus to stretch nuclear pores, resulting in prolonged nuclear accumulation of YAP/TAZ and amplification of mechanosensitive transcriptional outputs (iii) Mechanical feedback loop: The subclonal expansion drives aberrant cytoskeletal remodeling and fibrotic deposition, increasing pericardial stiffness. Enhanced mechanical stress further amplifies YAP/TAZ signaling, resulting in rapid, diffuse armor-like pericardial encasement.\u003c/p\u003e","description":"","filename":"SMARCA42.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/4e98639c08adefa65f21bd1a.png"},{"id":101001306,"identity":"5e707afb-ad16-4b92-8e18-9a6d8f54b2b1","added_by":"auto","created_at":"2026-01-23 16:36:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":599255,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed mechanobiological mechanism of pericardial encasement in SMARCA4-dNSCLC\u003c/strong\u003e. (i) Epigenetic dysregulation: SMARCA4/BRG1 deficiency disrupts SWI/SNF-mediated chromatin organization, leading to loss of epithelial lineage stability, increased transcriptional plasticity. (ii) YAP/TAZ activation and nuclear F-actin coupling: Loss of SMARCA4 impairs chromatin-mediated restraint of YAP/TAZ-TEAD-dependent transcription. Increased matrix stiffness or cytoskeletal tension from cyclic mechanical strain activate RhoA-ROCK signaling, promote F-actin polymerization, facilitating YAP/TAZ nuclear translocation by suppressing Hippo pathway and flattening the nucleus to stretch nuclear pores, resulting in prolonged nuclear accumulation of YAP/TAZ and amplification of mechanosensitive transcriptional outputs (iii) Mechanical feedback loop: The subclonal expansion drives aberrant cytoskeletal remodeling and fibrotic deposition, increasing pericardial stiffness. Enhanced mechanical stress further amplifies YAP/TAZ signaling, resulting in rapid, diffuse armor-like pericardial encasement.\u003c/p\u003e","description":"","filename":"SMARCA42.png","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/e27f3ac61c70135594613e1d.png"},{"id":102294828,"identity":"68457b4f-9860-499e-b24b-57c0be73b23a","added_by":"auto","created_at":"2026-02-10 09:59:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":33835978,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/f8ff3ebc-29c7-406c-b136-c213451a3421.pdf"},{"id":100964273,"identity":"a6e9e4d6-ff05-4581-aa6f-3cb75e9d709e","added_by":"auto","created_at":"2026-01-23 09:07:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29364,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarytable.docx","url":"https://assets-eu.researchsquare.com/files/rs-8666173/v1/29317865a1cb6b1f58323515.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eRapidly Progressive Pericardial Metastasis in SMARCA4-Deficient Non–Small Cell Lung Cancer: Implicating the SWI/SNF-YAP-EMT Axis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Patient prognosis and therapeutic responsiveness are strongly associated with specific genomic and epigenetic alterations. SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) has emerged as a distinct and clinically aggressive subtype, which is characterized by poor differentiation and dismal outcomes\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe SMARCA4 gene, located on chromosome 19p13.2, encodes the catalytic ATPase SMARCA4/BRG1, the core enzymatic subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. This complex plays a central role in regulating chromatin organization, transcription programs, DNA repair, and lineage maintenance\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Loss of SMARCA4 function, through genetic mutation, promoter methylation, or protein depletion, results in global transcriptional dysregulation, impairment of cell-cycle control, and enhanced cellular plasticity\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. These alterations are implicated in the pathogenesis of highly aggressive malignancies, including thoracic sarcomatoid tumors, and thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT).\u003c/p\u003e \u003cp\u003eSMARCA4-dNSCLC is clinically characterized by early metastatic dissemination, a high proliferative index, and limited sensitivity to standard chemotherapy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Emerging studies suggest that these tumors undergo metabolic reprogramming with increased reliance on oxidative phosphorylation\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. While mediastinal and pleural involvement are frequently observed, abrupt pericardial infiltration has rarely been described, and the biological mechanisms underlying this apparent serosal tropism remain poorly understood\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHere, we present a case of SMARCA4-dNSCLC marked by rapid and diffuse pericardial involvement that became the dominant driver of clinical deterioration. This report provides insight into the aggressive and non-linear disease kinetics associated with SMARCA4 deficiency and underscores the importance of early molecular recognition in guiding diagnostic and therapeutic decision-making.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 46-year-old male with a 30-pack-year smoking history was incidentally found to have multiple bilateral pulmonary nodular opacities during a workup for a thoracic vertebral fracture in Feburary 2025 (Month 0.0). Chest computed tomography (CT) demonstrated a 4.6*3.3 cm pretracheal mass posterior to the superior vena cava (SVC), with multiple mediastinal lymphadenopathies. Initial recommendations include re-examination and close observation.\u003c/p\u003e \u003cp\u003eBy Month 1.5, the patient developed dyspnea and was treated for suspected pneumonia with intravenous antibiotics for two months at an outside institution. A lack of symptomatic relief and the emergence of hemoptysis promoted repeat chest CT at Month 3.4, showing progression of the mediastinal lesions. Initial percutaneous lung biopsy was nondiagnostic and complicated by significant hemorrhage. Endobronchial ultrasound-guided needle aspiration (EBUS-TBNA) was performed on Month 5.0 demenstrated malignant epithelial cells. Immunohistochemistry (IHC) analysis revealed heterogeneous loss of SMARCA4/BRG1 (absent in the majority of tumor cells), and a Ki-67 proliferation index of appropriate 40%. Tumor cells were CK7 (+), TTF-1 (-), Napsin A (-), CK5/6 (-), and preserved INI-1 expression, consistent with SMARCA4-dNSCLC. Genomic profiling revealed no actionable driver mutations.\u003c/p\u003e \u003cp\u003ePercutaneous embolization of internal thoracic artery (Month 5.1) controlled refractory hemoptysis but was complicated by intraoperative atrial fibrilation, managed with lanatoside C. Thoracentesis (Month 5.2) revealed malignant plueral effusion. By Month 5.3, irregular atrial flutter and pericardial effusion emerged, confirmed by pericardial drainage (Month 5.4) as hemorrhagic and malignant. The patient and his family declined systemic chemotherapy and immunotherapy, receiving only palliative radiation therapy (30 Gy in 10 fractions, Month 5.4-6.0).\u003c/p\u003e \u003cp\u003eSerial imaging from Month 6.2 to Month 7.0 demenstrated rapid mediastianl mass growth (7.1*6.0 cm) with the SVC and right upper lobe vascular involvement, increased bilateral pleural effusions, and progressive circumferential pericardial thickening. The longitudinal clinical course timeline and radiographic progression is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At presentation, the pericardium appeared thin and unremarkable on chest CT. By Month 6.2, CT imaging revealed newly developed circumferential pericardial thickening, measuring 14.62 mm. At final CT (Month 9), the pericardium had formed an armor-like encasement of the heart, with maximal thickness up to 33.58 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). And representative transthoracic echocardiographic images are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC. By Month 8.5, echocardiography revealed persistent massive pericardial effusions and a new 2.2 *1.8 cm right upper lobe nodule. Laboratory evaluation indicated myocardial injury and systemic inflammation: WBC 23.3 \u0026times; 10^9/L, hemoglobin 76 g/L, IL-6 758.77 pg/mL, troponin I 0.34\u0026ndash;0.61 ng/mL, BNP 293.2 pg/mL, and D-dimer 2.28 mg/L.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePleural fliud cytology confirmed highly proliferative adenocarcinoma cells (MOC31 (+), Calretinin (-), TTF-1 (-), p40 (-), insulinoma-associated protein 1 (INSM1) (-), Napsin A (-), and Ki-67\u0026thinsp;~\u0026thinsp;90%) with heterogenous SMARCA4/BRG1 loss, consistent with aggressive SMARCA4-dNSCLC (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Despite supportive care, the patient died shortly after hospital discharge on Month 9.0. A detailed timeline of the clinical course is provided in Supplementary Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Disscussion","content":"\u003cp\u003eThe biological behavior of SMARCA4-dNSCLC represents a state of extreme oncogenic fitness. This case uniquely captures the uninterrupted natural history of the disease over a nine-month course. The disease evolved from relatively modest mediastinal mass into diffuse, circumferential pericardial encasement, revealing a distinctly non-linear kinetics.\u003c/p\u003e\n\u003ch3\u003eMechanistic considerations: the SMARCA4-YAP-EMT axis\u003c/h3\u003e\n\u003cp\u003eUnlike focal or hematogenous metastasis, which typically manifesting as pericardial effusion in pulmonary adenocarcinoma\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, this patient developed an armor-like infiltrative thickening of the pericardium. The aggressive phenotype observed can be partially attributed to heterogeneous loss of SMARCA4/BRG1. As the catalytic core of the SWI/SNF chromatin-remodeling complex, SMARCA4 maintains epithelial lineage fidelity through epihgenetic constraint\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Spatially incomplete or subclonal SMARCA4 loss increases transcriptional plasticity, allowing tumor cell subsets to acquire invasive and mesothelial-interactive properties\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Such epigenetic instability provides a permissive substrate for adaptation to non-parenchymal microenvironments, including pericardial surfaces\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMechanical signaling may further contributed to the unusual pericardial encasement observed in this case. The pericardium is a mechanically dynamic tissue, continuously exposed to cyclic stretch generated by cardiac motion\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Tumor cells infiltrating this environment are therefore subjected to persistent mechanical stress. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are central mediators of mechanical transduction\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Increased matrix stiffness or cytoskeletal tension from cyclic mechanical strain activate RhoA-ROCK signaling, promote F-actin polymerization, facilitating YAP/TAZ nuclear translocation by suppressing Hippo pathway and flattening the nucleus\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Nuclear YAP/TAZ then engage TEAD transcription factors to induce gene programs involved in epithelial-mesenchymal transition (EMT), a process by which epithelial tumor cells acquire invasive and migratory properties\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLoss of SMARCA4 alters this process at the chromatin level. Normally, SMARCA4-containing SWI/SNF complex restrains YAP/TAZ transcriptional output by maintaining a closed chromatin state at TEAD-bound enhancers and stabilizing epithelial lineage\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. SMARCA4 deficiency increases chromatin accessibility at YAP/TAZ-responsive loci, facilitating the constitutive recruitment of the YAP/TAZ-TEAD transcriptional complex. As a result, mechanical signals, such as cardiac cyclic strech, which would normally elicit limited responses or transient transcriptional responses, instead trigger amplified and sustained YAP/TAZ-driven EMT programs and matrix metalloproteinase (MMP) expression\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The accumulation of pericardial effusion may further increase tissue stiffness, establishing a self-reinforcing mechanobiological feedback loop (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWithin this mechanically constrained pericardial niche, SMARCA4-deficient subclones may therefore gain a competitive fitness advantage. This model provides a mechanistic explanation for the diffuse, armor-like pericardial expansion observed in this patient rather than focal nodular invasion. The resulting thickened, fibrotic remodeling and cardiac restriction became the dominant determinants of clinical deterioration and mortality. Further validation of this proposed mechanism will require spatially resolved transcriptomic analyses and biomechanically informed model systems.\u003c/p\u003e\n\u003ch3\u003eSMARCA4-dNSCLC versus SMARCA4-UT and potential therapeutic strategies\u003c/h3\u003e\n\u003cp\u003eAccurate distinction SMARCA4-dNSCLC and SMARCA4-UT is still a subject of debate. Unlike SMARCA4-UT, which typically demonstrates uniform SMARCA4 loss, rhabdoid morphology, and complete absence of epithelial differentiation, the present tumor retained adenocarcinoma morphology and expressed epithelial markers including CK7 and MOC31\u003csup\u003e6,18\u003c/sup\u003e. The heterogeneous SMARCA4/BRG1 loss supports a classification as SMARCA4-dNSCLC with loss of lineage-specific differentiation, rather than SMARCA4-UT\u003csup\u003e18\u003c/sup\u003e. And SMARCA4-dNSCLC is highly smoking-associated. This case underscores limitations of routine diagnostic workflows. Next-generation sequencing may fail to detect SMARCA4 alterations due to epigenetic silencing, or subclonal loss. Incorporation of SMARCA4immunohistochemistry into the initial diagnostic evaluation of high-grade thoracic tumors is therefore critical to avoid under-recognition of this aggressive subtype. Early recognition of SMARCA4-dNSCLC has direct prognostic and therapeutic implications, as SMARCA4-deficient tumor frequently exhibit rapid clinical deterioration that is poorly controlled by surgery and radiation\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTherapeutic options for SMARCA4-dNSCLC remain limited. Conventional platinum-based chemotherapy regimens offer modest efficacy, while immunetherapy outcomes are variable even in tumors with favorable fatures, such as heavy smoking history and high proliferative indices\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Preliminary data suggest that combining ICIs and chemotherapy with anlotinib may improve survival\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, yet identifying biomarkers to predict both ICIs efficacy and immune-related adverce events remains a critical need\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Translational studies have identified multiple downstream consequences of SMARCA4 loss, including epigenetic reprogramming involving BRCA1 impairment, pRB-associated cell-cycle dysregulation, and MYC-dependent transcriptional dependency\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. These insights have prompted preclinical exploration of epigenetic therapies. However, a standard of targeted approach has yet to be established for SMARCA4-deficient tumors.\u003c/p\u003e \u003cp\u003eIn this case, the pericardium acts as a mechanicalbiological niche favoring YAP/TAZ activation. SMARCA4 loss may sensitize tumor cells to these physical cues, enabling disproportionate invasive responses. This identifies a specific mechanobiological vulnerability worthy of further study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis report describes a fatal phenotype of SMARCA4-dNSCLC in which rapid pericardial invasion dominated clinical deterioration. The presentation underscores the marked biological plasticity associated with SMARCA4 deficiency. Early recognition of SMARCA4-deficient tumors is therefore essential. The pericardium-centered disease course suggests that loss of SMARCA4 may relax epigenetic constraints on periardial involvement, highlighting a potential avenue for future translational investigation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThere is no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eContributions of Authors\u003c/h2\u003e \u003cp\u003eS. Zhao contributed to conceiving the study, original manuscription writing, submission and clinical information collection. P. Tan and Y. Mu were involved in the management and follow-up of the patient. Song Tan provided funding.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics and Patient Consent Declaration\u003c/strong\u003e \u003cp\u003eThis study was approved by the Ethics Committee of Yantai Hospital of Traditional Chinese Medicine (Approval No. 2025-KY-027). The kin of patient consents to the publication using the clinical information. The kin has signed a form of patient consent for this case report publication.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eThans to he Department of Pathology at Yantai Hospital of Traditional Chinese Medicine for their technical assistance with histological examinations. This study was funded by the Natural Science Foundation of Shandong Province, China (Grant No. ZR2022LZY013). The proposed mechanistic figure is created in biorender.com. While preparing this work, the author used Open AI for the purpose of language polishment and to enhance the readability of the text. The author formally reviewed the content for its accuracy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchoenfeld AJ, Bandlamudi C, Lavery JA, Montecalvo J, Namakydoust A, Rizvi H, Egger J, Concepcion CP, Paul S, Arcila ME et al (2021) The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer. 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EMBO Mol Med 4:603\u0026ndash;616. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/emmm.201200236\u003c/span\u003e\u003cspan address=\"10.1002/emmm.201200236\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"aa99611f-0999-4ad1-af4a-bf2c7569d623","identifier":"10.13039/501100007129","name":"Natural Science Foundation of Shandong Province","awardNumber":"ZR2022LZY013","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Yantai Hospital of Traditional Chinese Medicine","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"SMARCA4, SWI/SNF, chromatin remodeling, YAP/TAZ, SMARCA4-dNSCLC; pericardial involvement","lastPublishedDoi":"10.21203/rs.3.rs-8666173/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8666173/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSMARCA4-deficient non–small cell lung cancer (SMARCA4-dNSCLC) is a rare and aggressive subtype with rapid progression and poor prognosis. Patterns of pericardial invasion and their biological mechanisms remain insufficiently characterized.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;A 46-year-old man presented with a mediastinal mass that enlarged from 4.9 cm to 7.1 cm over nine months. Despite relatively gradual enlargement of the primary lesion, the clinical course was abruptly dominated by diffuse pericardial involvement. Serial imaging demonstrated circumferential, infiltrative pericardial thickening with an armor-like configration, leading to restrictive cardiac physiology and fatal hemodynamic compromise. Cytological and immunohistochemical revealed malignant epithelial cells with TTF-1 (-), p40 (-), CK7 (+), and MOC31 (+), accompanied by markedly elevated proliferative index of Ki-67. Heterogeneous loss of SMARCA4/BRG1 confirmed the diagnosis of SMARCA4-dNSCLC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case illustrates a pericardial, non-linear progression pattern in SMARCA4-dNSCLC. Early recognition of SMARCA4 deficiency through SMARCA4/BRG1 immunohistochemistry is essential, as such aggressive kinetics may warrant early systemic evaluation. This case supports a hypothesis that SMARCA4 deficiency sensitizes cells to YAP-driven EMT program, while cardicac-derived mechanical strech provides a permissive microenvironment, synergistically contributing to the aggressive, armor-like pericardial thickening in this malignancy.\u003c/p\u003e","manuscriptTitle":"Rapidly Progressive Pericardial Metastasis in SMARCA4-Deficient Non–Small Cell Lung Cancer: Implicating the SWI/SNF-YAP-EMT Axis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-23 09:07:11","doi":"10.21203/rs.3.rs-8666173/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"99e0a3d9-037e-4fff-9b7d-e4fe48a8f599","owner":[],"postedDate":"January 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61560676,"name":"Epigenetics \u0026 Genomics"},{"id":61560677,"name":"Oncology"},{"id":61560678,"name":"Translational Medicine"}],"tags":[],"updatedAt":"2026-01-23T09:07:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-23 09:07:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8666173","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8666173","identity":"rs-8666173","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}