AUTHOR=Rafaeva Maria , Jensen Adina R. D. , Horton Edward R. , Zornhagen Kamilla W. , Strøbech Jan E. , Fleischhauer Lutz , Mayorca-Guiliani Alejandro E. , Nielsen Sebastian R. , Grønseth Dina S. , Kuś Filip , Schoof Erwin M. , Arnes Luis , Koch Manuel , Clausen-Schaumann Hauke , Izzi Valerio , Reuten Raphael , Erler Janine T. TITLE=Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1154528 DOI=10.3389/fimmu.2023.1154528 ISSN=1664-3224 ABSTRACT=

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.