Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression

• DOI: 10.3389/fimmu.2023.1154528
• Publication Date: 2023-07-18T10:54:07Z
• Authors: Maria Rafaeva; Adina R. D. Jensen; Edward R. Horton; Kamilla W. Zornhagen; Jan E. Strøbech; Lutz Fleischhauer; Alejandro E. Mayo...; Sebastian R. Nielsen; Dina S. Grønseth; Filip Kuś; Erwin M. Schoof; Luis Arnes; Manuel Koch; Hauke Clausen-Sch...; Valerio Izzi; Raphael Reuten; Janine T. Erler
• Keywords: Extracellular Matrix Proteins; desmoplasia; extracellular matrix; pancreatic cancer; Immunology; 610; Extracellular matrix; Pancreatic cancer; RC581-607; Fibroblasts; Mechanics; Prognosis; Desmoplasia; 3. Good health; Pancreatic Neoplasms; models; breast cancer; Breast cancer; Models; fibroblasts; Humans; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being; Immunologic diseases. Allergy; mechanics; Carcinoma, Pancreatic Ductal

The desmoplastic reaction observed in many cancers is a hallmark of disease progression and prognosis, particularly in breast and pancreatic cancer. Stromal-derived extracellular matrix (ECM) is significantly altered in desmoplasia, and as such plays a critical role in driving cancer progression. Using fibroblast-derived matrices (FDMs), we show that cancer cells have increased growth on cancer associated FDMs, when compared to FDMs derived from non-malignant tissue (normal) fibroblasts. We assess the changes in ECM characteristics from normal to cancer-associated stroma at the primary tumor site. Compositional, structural, and mechanical analyses reveal significant differences, with an increase in abundance of core ECM proteins, coupled with an increase in stiffness and density in cancer-associated FDMs. From compositional changes of FDM, we derived a 36-ECM protein signature, which we show matches in large part with the changes in pancreatic ductal adenocarcinoma (PDAC) tumor and metastases progression. Additionally, this signature also matches at the transcriptomic level in multiple cancer types in patients, prognostic of their survival. Together, our results show relevance of FDMs for cancer modelling and identification of desmoplastic ECM components for further mechanistic studies.