Integration of cell-type resolved spatial proteomics and transcriptomics reveals novel mechanisms in early ovarian cancer

Abstract High-grade serous carcinoma (HGSC) is the most common ovarian cancer subtype, typically diagnosed at late stages with poor prognosis. Understanding early molecular events driving HGSC progression is crucial for timely detection and development of effective treatment strategies. We performed and integrated spatial cell-type resolved proteomics and paired transcriptomics across 25 women with precursor lesions of the fallopian tube and/or HGSC. Epithelial cell signatures revealed early activation of SUMOylation machinery, increased ATR and Wnt signaling, and enhanced MHC-I antigen presentation along the disease trajectory. The stroma exhibited extracellular matrix remodeling and interferon-mediated inflammation. Serous tubal intraepithelial carcinomas (STICs) in cancer patients contained a pro-coagulative signature and reduced APOA1/2 compared to STICs in individuals without cancer. We functionally established important roles of epithelial-derived TRIP13 and SUMOylation, and cancer-associated fibroblast-derived SULF1 and BGN in HGSC progression. These findings provide unique molecular insights into HGSC pathogenesis and identify potential new therapeutic targets for intervention. Competing Interest Statement L.S. is a current employee of OmicVision Biosciences ApS. F.J.T. consults for Immunai Inc., Singularity Bio B.V., CytoReason Ltd, Cellarity, and has ownership interest in Dermagnostix GmbH and Cellarity. MM is an indirect investor in Evosep and OmicVision Biosciences ApS. The other authors declare no potential conflicts of interest in the context of this manuscript. Funding Statement This work was supported by the Max Planck Society for the Advancement of Science. Andreas Metousis is supported by a PhD scholarship from the Onassis Foundation (Scholarship ID: F ZS 031-1/2022-2023) and by an interdisciplinary life science fellowship awarded by the Joachim Herz Stiftung. This research was funded by an NIH/NCI R35 grant (CA264619, E Lengyel), generous philanthropic donations from Linda Usher and family (SD Yamada), Bears Care - the charitable beneficiary of the Chicago Bears Football Club (H. Kenny and E. Lengyel), and the Janet Burros Foundation (E. Lengyel). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has received IRB/Ethics approval from the University of Chicago and the Max Planck Institute. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Spatial proteomics data are deposited in the PRIDE database (ProteomeXchange: PXD062349) and spatial transcriptomics data in GEO (GSE305176). Pseudonymized datasets will be publicly released upon publication.