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Inter‐ and intra‐tumoural heterogeneity in cancer‐associated fibroblasts of human pancreatic ductal adenocarcinoma
Open accessAbstract
Cancer‐associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro‐ versus anti‐tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient‐derived CAF primary cultures, we demonstrated that human PDAC‐derived CAFs display a high level of inter‐ and intra‐tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC‐derived CAFs (pCAFassigner). Multiple CAF subtypes co‐existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix‐ and immune‐related signatures, vimentin and α‐smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non‐tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF‐like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter‐ and intra‐tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single‐cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Cites
Molecular signatures database (MSigDB) 3.0
Liberzon, A., Subramanian, A., Pinchback, R., Thorvaldsdóttir, H., Tamayo, P., & Mesirov, J. P. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr260 · Cited by 7,111
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621 · cited 11×
“The International Cancer Genome Consortium (ICGC) dataset from Bailey et al [12], comprising 96 pancreatic samples (RNAseq), was used to assign pCAFassigner subtypes using PAM centroids generated from CAF primary cultures.”
BackgroundMethodInfluentialÖzdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.005 · Cited by 2,681
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590
Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3398 · Cited by 2,194
Integrated genomic characterization of pancreatic ductal adenocarcinoma
Raphael, B. J., Hruban, R. H., Aguirre, A. J., Moffitt, R. A., Yeh, J. J., Stewart, C., Robertson, A. G., Cherniack, A. D., Gupta, M., Getz, G., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.07.007 · Cited by 2,019
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705 · cited 1×
“In breast cancer, CAF subtypes have already been proposed as predictive markers of response to immune therapy [52].”
BackgroundPhenotype molding of stromal cells in the lung tumor microenvironment
Lambrechts, D., Wauters, E., Boeckx, B., Aibar, S., Nittner, D., Burton, O., Bassez, A., Decaluwé, H., Pircher, A., Van den Eynde, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0096-5 · Cited by 1,648
Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., Wang, M., Luo, M., Xing, Y., Chen, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.009 · Cited by 1,230
Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C., Marshall, J. F., Chin–Aleong, J., Chelala, C., Gribben, J. G., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.025 · Cited by 579
Self-citation
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Mao, X., Xu, J., Wang, W., Liang, C., Hua, J., Liu, J., Zhang, B., Meng, Q., Yu, X., & Shi, S. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01428-1 · Cited by 2,290
Diversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265
Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer.
Kieffer, Y., Hocine, H. R., Gentric, G., Pelon, F., Bernard, C., Bourachot, B., Lameiras, S., Albergante, L., Bonneau, C., Guyard, A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1384 · Cited by 910
Cancer-associated fibroblasts in the single-cell era
Lavie, D., Ben-Shmuel, A., Erez, N., & Scherz-Shouval, R. (2022) · Nature Cancer · doi:10.1038/s43018-022-00411-z · Cited by 616
Cancer-associated fibroblasts: from basic science to anticancer therapy
Yang, D., Liu, J., Qian, H., & Zhuang, Q. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01013-0 · Cited by 572
Fibroblasts in cancer: Unity in heterogeneity
Chhabra, Y., & Weeraratna, A. T. (2023) · Cell · doi:10.1016/j.cell.2023.03.016 · Cited by 474
Microenvironmental Determinants of Pancreatic Cancer
Hessmann, E., Buchholz, S. M., Demir, I. E., Singh, S. K., Gress, T. M., Ellenrieder, V., & Neesse, A. (2020) · Physiological Reviews · doi:10.1152/physrev.00042.2019 · Cited by 331
(2022) · doi:10.1158/2159-8290.cd-20-1484 · Cited by 311
Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment
Helms, E., Onate, M. K., & Sherman, M. H. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1353 · Cited by 283
CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities
Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R., Siegler, E. L., & Kenderian, S. S. (2022) · Molecular Therapy - Oncolytics · doi:10.1016/j.omto.2022.03.009 · Cited by 282
Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies
Mhaidly, R., & Mechta-Grigoriou, F. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101417 · Cited by 259
Mhaidly, R., & Mechta‐Grigoriou, F. (2021) · Immunological Reviews · doi:10.1111/imr.12978 · Cited by 231
The mesenchymal context in inflammation, immunity and cancer
Koliaraki, V., Prados, A., Armaka, M., & Kollias, G. (2020) · Nature Immunology · doi:10.1038/s41590-020-0741-2 · Cited by 253
Helms, E. J., Berry, M. W., Chaw, R. C., DuFort, C. C., Sun, D., Onate, M. K., Oon, C., Bhattacharyya, S., Sanford-Crane, H., Horton, W., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0601 · Cited by 238
Grauel, A. L., Nguyen, B., Ruddy, D., Laszewski, T., Schwartz, S., Chang, J., Chen, J., Piquet, M., Pelletier, M., Yan, Z., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19920-5 · Cited by 211
Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy
Raskov, H., Orhan, A., Gaggar, S., & Gögenur, I. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.668731 · Cited by 150
Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context
Kerk, S. A., Lin, L., Myers, A. L., Sutton, D. J., Andren, A., Sajjakulnukit, P., Zhang, L., Zhang, Y., Jiménez, J. A., Nelson, B. S., et al. (2022) · eLife · doi:10.7554/elife.73245 · Cited by 108
Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma
Garcia, P. E., Adoumie, M., Kim, E. C., Zhang, Y., Scales, M. K., El-Tawil, Y. S., Shaikh, A. Z., Wen, H.-J., Bednar, F., Allen, B. L., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.05.004 · Cited by 110
Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment
Brown, N. F., & Marshall, J. F. (2019) · Cancers · doi:10.3390/cancers11091221 · Cited by 116
Determinants and functions of CAFs secretome during cancer progression and therapy
Linares, J., Marín-Jiménez, J. A., Badia-Ramentol, J., & Calon, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.621070 · Cited by 110
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108
Shaashua, L., Ben-Shmuel, A., Pevsner-Fischer, M., Friedman, G., Levi-Galibov, O., Nandakumar, S., Barki, D., Nevo, R., Brown, L. E., Zhang, W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34081-3 · Cited by 79
Current Status of Research on Losartan in Tumour Therapy
Wang, H., Yuan, S., & Wang, H. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70985 · Cited by 11
Metadata
- Authors
- Neuzillet, C., Tijeras‐Raballand, A., Ragulan, C., Cros, J., Patil, Y., Martinet, M., Erkan, M., Kleeff, J., Wilson, J., Apte, M., Tosolini, M., Wilson, A. S., Delvecchio, F. R., Bousquet, C., Paradis, V., Hammel, P., Sadanandam, A., & Kocher, H. M.
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2019-02-22
- Volume
- 248
- Issue
- 1
- Pages
- 51-65
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W2905888775
- Cited by
- 295
- References
- 12
- FWCI
- 10.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
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