Abstract
Tumors initiate by mutations in cancer cells, and progress through interactions of the cancer cells with non-malignant cells of the tumor microenvironment. Major players in the tumor microenvironment are cancer-associated fibroblasts (CAFs), which support tumor malignancy, and comprise up to 90% of the tumor mass in pancreatic cancer. CAFs are transcriptionally rewired by cancer cells. Whether this rewiring is differentially affected by different mutations in cancer cells is largely unknown. Here we address this question by dissecting the stromal landscape of BRCA-mutated and BRCA Wild-type pancreatic ductal adenocarcinoma. We comprehensively analyze pancreatic cancer samples from 42 patients, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA Wild-type tumors. In particular, we detect an increase in a subset of immune-regulatory clusterin-positive CAFs in BRCA-mutated tumors. Using cancer organoids and mouse models we show that this process is mediated through activation of heat-shock factor 1, the transcriptional regulator of clusterin. Our findings unravel a dimension of stromal heterogeneity influenced by germline mutations in cancer cells, with direct implications for clinical research.
| Original language | English |
|---|---|
| Article number | 6513 |
| Journal | Nature Communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
| Externally published | Yes |
Bibliographical note
Funding Information:Bioinformatic analyses were assisted by Ester Feldmesser, Ron Rotkopf, and Irit Orr (WIS). The authors thank Ela Elyada and Giulia Biffi for their guidance with the organoid system, and all members of the Scherz-Shouval lab for their valuable input. We thank Ofra Golani at the MICC cell observatory, WIS, and Dr. Liat Alyagor, Immunohistochemistry unit, WIS for their assistance with imaging. We thank Dr. Yishai Levin from the De Botton Protein Profiling institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, WIS, for his assistance with mass spectrometry analysis. We thank Ms. Ariela Tomer for assistance in patient recruitment and sample collection. RSS is supported by the Thompson Family Foundation, ISF grant 395/21, ERC grant 754320, the Laura Gurwin Flug Family Fund, the Peter and Patricia Gruber Awards, the Comisaroff Family Trust, the Estate of Annice Anzelewitz, and the Estate of Mordecai M. Roshwal. RSS is the incumbent of the Ernst and Kaethe Ascher Career Development Chair in Life Sciences. LS was supported by the Rising Tide Foundation. DK was supported by MSK Center Core Grant P30 CA008748 and data science grant. Work at Boston University was supported by NIH grants R35GM118173 and U01TR002625.
Funding Information:
Bioinformatic analyses were assisted by Ester Feldmesser, Ron Rotkopf, and Irit Orr (WIS). The authors thank Ela Elyada and Giulia Biffi for their guidance with the organoid system, and all members of the Scherz-Shouval lab for their valuable input. We thank Ofra Golani at the MICC cell observatory, WIS, and Dr. Liat Alyagor, Immunohistochemistry unit, WIS for their assistance with imaging. We thank Dr. Yishai Levin from the De Botton Protein Profiling institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, WIS, for his assistance with mass spectrometry analysis. We thank Ms. Ariela Tomer for assistance in patient recruitment and sample collection. RSS is supported by the Thompson Family Foundation, ISF grant 395/21, ERC grant 754320, the Laura Gurwin Flug Family Fund, the Peter and Patricia Gruber Awards, the Comisaroff Family Trust, the Estate of Annice Anzelewitz, and the Estate of Mordecai M. Roshwal. RSS is the incumbent of the Ernst and Kaethe Ascher Career Development Chair in Life Sciences. LS was supported by the Rising Tide Foundation. DK was supported by MSK Center Core Grant P30 CA008748 and data science grant. Work at Boston University was supported by NIH grants R35GM118173 and U01TR002625.
Publisher Copyright:
© 2022, The Author(s).
