Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 1154528 |
| Tidsskrift | Frontiers in Immunology |
| Vol/bind | 14 |
| Antal sider | 12 |
| ISSN | 1664-3224 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by a PhD fellowship from the Lundbeck Foundation (MR: R286-2018-621), the Danish Council for Independent Research YDUN grant (AJ; 1084181001), the European Research Council (MR, AJ, EH, JS, AM-G, SN, RR, JE: ERC-2015-CoG-682881-MATRICAN), the Danish Cancer Society (SN: R167-A10618; EH: R204-A12445; RR: R204-A12454), the European Molecular Biology Organization (EH: ALTF 922-2016), a Novo Nordisk Foundation Hallas Møller Stipend (JE), and the German Cancer Aid (RR). LF and HC-S acknowledge funding from the Bavarian State Ministry for Science and Art through the Research Focus “Angewandte Photonik” and the Bavarian Academic Forum (BayWISS)—Doctoral Consortium “Health Research”. The Cancer Society of Finland (VI: 63-6445) (VI). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
Funding Information:
This work was supported by a PhD fellowship from the Lundbeck Foundation (MR: R286-2018-621), the Danish Council for Independent Research YDUN grant (AJ; 1084181001), the European Research Council (MR, AJ, EH, JS, AM-G, SN, RR, JE: ERC-2015-CoG-682881-MATRICAN), the Danish Cancer Society (SN: R167-A10618; EH: R204-A12445; RR: R204-A12454), the European Molecular Biology Organization (EH: ALTF 922-2016), a Novo Nordisk Foundation Hallas Møller Stipend (JE), and the German Cancer Aid (RR). LF and HC-S acknowledge funding from the Bavarian State Ministry for Science and Art through the Research Focus “Angewandte Photonik” and the Bavarian Academic Forum (BayWISS)—Doctoral Consortium “Health Research”. The Cancer Society of Finland (VI: 63-6445) (VI). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Acknowledgments
Publisher Copyright:
Copyright © 2023 Rafaeva, Jensen, Horton, Zornhagen, Strøbech, Fleischhauer, Mayorca-Guiliani, Nielsen, Grønseth, Kuś, Schoof, Arnes, Koch, Clausen-Schaumann, Izzi, Reuten and Erler.
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