Intratumoral viable biological agent as a Multi-Mechanism Therapeutic Strategy for Pancreatic Adenocarcinoma

Intratumoral viable biological agent as a Multi-Mechanism Therapeutic Strategy for Pancreatic Adenocarcinoma | 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 Research Article Intratumoral viable biological agent as a Multi-Mechanism Therapeutic Strategy for Pancreatic Adenocarcinoma Murad Novruzov, Marziyya Mammadova, Keval Raval, Waseem Ullah Khan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8768147/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: Pancreatic ductal adenocarcinoma (PDAC) exhibits five-year survival rates below 10% with profound therapeutic resistance mediated by stromal barriers and immunosuppression [1,2]. Recent evidence suggests intratumoral mycobiome alterations may influence disease progression [17,18]. Methods: We performed comprehensive network pharmacology analysis to elucidate potential therapeutic mechanisms of Saccharomyces boulardii (SB) and Clostridium histolyticum collagenase (CHC) in PDAC. Gene sets representing immune activation, metabolic competition, and stromal remodeling were analyzed using protein-protein interaction networks (STRING v11.5), functional enrichment (DAVID v2021), and pathway databases (KEGG, Reactome, WikiPathways, DisGeNET). Results: Network analysis identified dense interconnectivity among 20 core immune-metabolic genes with hub proteins TNF, IL6, IFNG, and TLR4 (degree >15). Key intersecting genes between SB and CHC mechanisms included IL6, TLR2, MMP9, and IL1B. Pathway enrichment revealed significant involvement in IL-17 signaling pathway (hsa04657), Toll-like receptor signaling (hsa04620), viral protein interaction with cytokines (hsa04061), interleukin-10 signaling (fold enrichment = 184.61, p=4.47×10−31 p =4.47×10−31), and immune infiltration in pancreatic cancer (WP5285). Co-occurrence analysis across 10,897 tumors revealed coordinated expression of IFNG-TLR4 and IFNG-CD86 gene pairs. Conclusions: Network analysis supports biological plausibility of multi-mechanism SB anti-tumor activity through convergent immune activation, metabolic competition, and stromal remodeling pathways complemented by CHC-mediated extracellular matrix disruption. This systems-level framework provides mechanistic rationale for empirical investigation. Computational Biology Cancer Biology Immunology Bioinformatics network pharmacology pancreatic cancer Saccharomyces boulardii collagenase systems biology pathway enrichment Full Text Additional Declarations The authors declare no competing interests. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8768147","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":584556952,"identity":"893556f0-402c-4129-b314-65ab0a61d027","order_by":0,"name":"Murad Novruzov","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYBCDBH4wxUaKFskGkrUYHCBWi3l7+8MHP/fY5RlfO2P24UfZHTmD22eMP3xsY5Az71+AVYvMmTPGhj3PkovNbucYz+w598zY4FyOgeHMNgZjmRsPsGqRkMhhk+A5cCBxG1ALA2/b4cSZPTwGyTxnGBJnSBzArkX++fOff4BaNs/OMWb8C9VyGK8WCQYzZpAtG6RzjJlBtvTz8Bg281QAtfA3YNfCk2MsLXMgOXHG7bRiZplzh435ediKGWdUSBgDTcOuhf34w49vDtgl9s9O3sz4puywHBsP8+YPHwxs5CT4sTsMJwBaIZFAmhYgINWWUTAKRsEoGK4AAETMXHwNvxeyAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0007-2386-6332","institution":"Murad Novruzov Biomedical Research","correspondingAuthor":true,"prefix":"","firstName":"Murad","middleName":"","lastName":"Novruzov","suffix":""},{"id":584557054,"identity":"a9bf5184-fb5c-4a45-a7b0-353c77023295","order_by":1,"name":"Marziyya Mammadova","email":"","orcid":"https://orcid.org/0000-0001-5976-6551","institution":"Azerbaijan State Advanced Training Institute for Doctors named after Aziz Aliyev - 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Recent evidence suggests intratumoral mycobiome alterations may influence disease progression [17,18].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u0026nbsp;We performed comprehensive network pharmacology analysis to elucidate potential therapeutic mechanisms of Saccharomyces boulardii\u0026nbsp;(SB) and Clostridium histolyticum\u0026nbsp;collagenase (CHC) in PDAC. Gene sets representing immune activation, metabolic competition, and stromal remodeling were analyzed using protein-protein interaction networks (STRING v11.5), functional enrichment (DAVID v2021), and pathway databases (KEGG, Reactome, WikiPathways, DisGeNET).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;Network analysis identified dense interconnectivity among 20 core immune-metabolic genes with hub proteins TNF, IL6, IFNG, and TLR4 (degree \u0026gt;15). Key intersecting genes between SB and CHC mechanisms included IL6, TLR2, MMP9, and IL1B. Pathway enrichment revealed significant involvement in IL-17 signaling pathway (hsa04657), Toll-like receptor signaling (hsa04620), viral protein interaction with cytokines (hsa04061), interleukin-10 signaling (fold enrichment = 184.61, p=4.47×10−31\u003cem\u003ep\u003c/em\u003e=4.47×10−31), and immune infiltration in pancreatic cancer (WP5285). Co-occurrence analysis across 10,897 tumors revealed coordinated expression of IFNG-TLR4 and IFNG-CD86 gene pairs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u0026nbsp;Network analysis supports biological plausibility of multi-mechanism SB anti-tumor activity through convergent immune activation, metabolic competition, and stromal remodeling pathways complemented by CHC-mediated extracellular matrix disruption. 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