Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
06 Apr 2024
06 Apr 2024
Historique:
received:
08
09
2023
accepted:
22
03
2024
revised:
21
03
2024
medline:
7
4
2024
pubmed:
7
4
2024
entrez:
6
4
2024
Statut:
aheadofprint
Résumé
Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small cell lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations of CAFs, which can influence prognosis and treatment efficacy. We describe the subtypes of CAFs in NSCLC. Primary human NSCLC resections were assessed by flow cytometry and multiplex immunofluorescence for markers of fibroblast activation which allowed identification of CAF subsets. Survival data were analysed for our NSCLC cohort consisting of 163 patients to understand prognostic significance of CAF subsets. We identified five CAF populations, termed CAF S1-S5. CAF-S5 represents a previously undescribed population, and express FAP and PDPN but lack the myofibroblast marker αSMA, whereas CAF-S1 populations express all three. CAF-S5 are spatially further from tumour regions then CAF-S1 and scRNA data demonstrate an inflammatory phenotype. The presence of CAF-S1 or CAF-S5 is correlated to worse survival outcome in NSCLC, despite curative resection, highlighting the prognostic importance of CAF subtypes in NSCLC. TCGA data suggest the predominance of CAF-S5 has a poor prognosis across several cancer types. This study describes the fibroblast heterogeneity in NSCLC and the prognostic importance of the novel CAF-S5 subset where its presence correlates to worse survival outcome.
Sections du résumé
BACKGROUND
BACKGROUND
Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small cell lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations of CAFs, which can influence prognosis and treatment efficacy. We describe the subtypes of CAFs in NSCLC.
METHODS
METHODS
Primary human NSCLC resections were assessed by flow cytometry and multiplex immunofluorescence for markers of fibroblast activation which allowed identification of CAF subsets. Survival data were analysed for our NSCLC cohort consisting of 163 patients to understand prognostic significance of CAF subsets.
RESULTS
RESULTS
We identified five CAF populations, termed CAF S1-S5. CAF-S5 represents a previously undescribed population, and express FAP and PDPN but lack the myofibroblast marker αSMA, whereas CAF-S1 populations express all three. CAF-S5 are spatially further from tumour regions then CAF-S1 and scRNA data demonstrate an inflammatory phenotype. The presence of CAF-S1 or CAF-S5 is correlated to worse survival outcome in NSCLC, despite curative resection, highlighting the prognostic importance of CAF subtypes in NSCLC. TCGA data suggest the predominance of CAF-S5 has a poor prognosis across several cancer types.
CONCLUSION
CONCLUSIONS
This study describes the fibroblast heterogeneity in NSCLC and the prognostic importance of the novel CAF-S5 subset where its presence correlates to worse survival outcome.
Identifiants
pubmed: 38582812
doi: 10.1038/s41416-024-02671-1
pii: 10.1038/s41416-024-02671-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : RCUK | Engineering and Physical Sciences Research Council (EPSRC)
ID : EP/L016559/1
Informations de copyright
© 2024. The Author(s).
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
doi: 10.3322/caac.21660
pubmed: 33538338
Molina JR. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–94. www.mayoclinicproceedings.com584 .
doi: 10.1016/S0025-6196(11)60735-0
pubmed: 18452692
Iglesias VS, Giuranno L, Dubois LJ, Theys J, Vooijs M. Drug resistance in non-small cell lung cancer: a potential for NOTCH targeting? Front Oncol. 2018;8:267. www.frontiersin.org .
doi: 10.3389/fonc.2018.00267
Bremnes RM, Dønnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, et al. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol. 2011;6:209–17. https://doi.org/10.1097/JTO.0b013e3181f8a1bd .
doi: 10.1097/JTO.0b013e3181f8a1bd
pubmed: 21107292
Castells M, Thibault B, Delord JP, Couderc B. Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci. 2012;13:9545–71. http://www.mdpi.com/1422-0067/13/8/9545/ .
doi: 10.3390/ijms13089545
pubmed: 22949815
pmcid: 3431813
Hu H, Piotrowska Z, Hare PJ, Chen H, Mulvey HE, Mayfield A, et al. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms. Cancer Cell. 2021;39:1531–47.e10.
doi: 10.1016/j.ccell.2021.09.003
pubmed: 34624218
pmcid: 8578451
Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 2020;10:232–53. http://aacrjournals.org/cancerdiscovery/article-pdf/10/2/232/1804634/232.pdf .
Santi A, Kugeratski FG, Zanivan S. Cancer associated fibroblasts: the architects of stroma remodeling. Proteomics. 2018;18:e1700167.
Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20:174–86. https://doi.org/10.1038/s41568-019-0238-1 .
doi: 10.1038/s41568-019-0238-1
pubmed: 31980749
pmcid: 7046529
Kalluri R. The biology and function of fibroblasts in cancer. Nat Publ Gr. 2016. www.nature.com/nrc .
Monteran L, Erez N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front Immunol. 2019;10:1–15.
doi: 10.3389/fimmu.2019.01835
Joshi RS, Kanugula SS, Sudhir S, Pereira MP, Jain S, Aghi MK. The role of cancer-associated fibroblasts in tumor progression. 2021. https://doi.org/10.3390/cancers13061399 .
Mathieson L, O’Connor RA, Stewart H, Shaw P, Dhaliwal K, Williams GOS, et al. Fibroblast activation protein specific optical imaging in non-small cell lung cancer. Front Oncol. 2022;12:1–10.
doi: 10.3389/fonc.2022.834350
O’Connor RA, Chauhan V, Mathieson L, Titmarsh H, Koppensteiner L, Young I, et al. T cells drive negative feedback mechanisms in cancer associated fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer. Oncoimmunology. 2021;10:1940675.
O’Connor RA, Martinez BR, Koppensteiner L, Mathieson L, Akram AR. Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta. Front Immunol. 2023;14:1221532.
Mhaidly R, Mechta-Grigoriou F. Fibroblast heterogeneity in tumor micro-environment: role in immunosuppression and new therapies. Semin Immunol. 2020;48:101417.
Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96.
doi: 10.1084/jem.20162024
pubmed: 28232471
pmcid: 5339682
Chen PY, Wei WF, Wu HZ, Fan LS, Wang W. Cancer-associated fibroblast heterogeneity: a factor that cannot be ignored in immune microenvironment remodeling. Front Immunol. 2021;12:2760.
Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–79.e10.
doi: 10.1016/j.ccell.2018.01.011
pubmed: 29455927
Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I, et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat Commun. 2020;11. https://doi.org/10.1038/s41467-019-14134-w .
Givel AM, Kieffer Y, Scholer-Dahirel A, Sirven P, Cardon M, Pelon F, et al. MiR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat Commun. 2018;9. https://doi.org/10.1038/s41467-018-03348-z .
Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018;24:1277–89. https://doi.org/10.1038/s41591-018-0096-5 .
doi: 10.1038/s41591-018-0096-5
pubmed: 29988129
Grout JA, Sirven P, Leader AM, Maskey S, Hector E, Puisieux I, et al. Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors. Cancer Discov. 2022;12:2606–25.
Bartoschek M, Oskolkov N, Bocci M, Lövrot J, Larsson C, Sommarin M, et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018;9. www.nature.com/naturecommunications .
Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts antigen-presenting CAFs in PDAC. Cancer Discov. 2019;9:1102–25. www.aacrjournals.org .
doi: 10.1158/2159-8290.CD-19-0094
pubmed: 31197017
pmcid: 6727976
Li H, Courtois ET, Sengupta D, Tan Y, Chen KH, Goh JJL, et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat Genet. 2017;49:708–18.
Neuzillet C, Tijeras-Raballand A, Ragulan C, Cros J, Patil Y, Martinet M, et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J Pathol. 2019;248:51–65.
doi: 10.1002/path.5224
pubmed: 30575030
pmcid: 6492001
McInnes L, Healy J, Melville J. UMAP: uniform manifold approximation and projection for dimension reduction. 2018. http://arxiv.org/abs/1802.03426 .
Van Gassen S, Callebaut B, Van Helden MJ, Lambrecht BN, Demeester P, Dhaene T, et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytom Part A. 2015;87:636–45.
doi: 10.1002/cyto.a.22625
Titmarsh HF, von Kriegsheim A, Wills JC, O’Connor RA, Dhaliwal K, Frame MC, et al. Quantitative proteomics identifies tumour matrisome signatures in patients with non-small cell lung cancer. Front Oncol. 2023;13:1–14.
doi: 10.3389/fonc.2023.1194515
Koppensteiner L, Mathieson L, Pattle S, Dorward DA, O’Connor RA, Akram AR. Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer. J Immunother Cancer. 2023;11:e006770.
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:1–7. https://www.nature.com/articles/s41598-017-17204-5 .
doi: 10.1038/s41598-017-17204-5
Schmidt U, Weigert M, Broaddus C, Myers G. Cell detection with star-convex polygons. 2018. https://doi.org/10.1007/978-3-030-00934-2_30 .
Wu F, Fan J, He Y, Xiong A, Yu J, Li Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun. 2021;12:1–11.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:1–21.
doi: 10.1186/s13059-014-0550-8
Mhaidly R, Mechta-Grigoriou F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunol Rev. 2021;302:259–72.
doi: 10.1111/imr.12978
pubmed: 34013544
pmcid: 8360036
Sorin M, Rezanejad M, Karimi E, Fiset B, Desharnais L, Perus LJM, et al. Single-cell spatial landscapes of the lung tumour immune microenvironment. Nature. 2023;614:548–54.
doi: 10.1038/s41586-022-05672-3
pubmed: 36725934
pmcid: 9931585
Astarita JL, Acton SE, Turley SJ. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol. 2012;3:1–11.
doi: 10.3389/fimmu.2012.00283
Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell. 2006;9:261–72.
doi: 10.1016/j.ccr.2006.03.010
pubmed: 16616332
Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008;123:1053–9. www.interscience .
doi: 10.1002/ijc.23611
pubmed: 18546264
Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac K, Woodruff MC, et al. FAP delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol Res. 2018;6:1472–85.
doi: 10.1158/2326-6066.CIR-18-0098
pubmed: 30266714
pmcid: 6597261
Costa A, Kieffer Y, Scholer-dahirel A, Soumelis V, Vincent-salomon A, Costa A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–79.e10. https://doi.org/10.1016/j.ccell.2018.01.011 .
doi: 10.1016/j.ccell.2018.01.011
pubmed: 29455927
Buechler MB, Pradhan RN, Krishnamurty AT, Cox C, Calviello AK, Wang AW, et al. Cross-tissue organization of the fibroblast lineage. Nature. 2021;593:575–9. https://doi.org/10.1038/s41586-021-03549-5 .
doi: 10.1038/s41586-021-03549-5
pubmed: 33981032
Kilvaer TK, Khanehkenari MR, Hellevik T, Al-Saad S, Paulsen EE, Bremnes RM, et al. Cancer associated fibroblasts in stage I-IIIA NSCLC: prognostic impact and their correlations with tumor molecular markers. PLoS ONE. 2015;10. https://doi.org/10.1371/journal.pone.0134965 .
Kilvaer TK, Rakaee M, Hellevik T, Østman A, Strell C, Bremnes RM, et al. Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer. PLoS ONE. 2018;13:1–17.
doi: 10.1371/journal.pone.0192157
Moreno-Ruiz P, Corvigno S, te Grootenhuis NC, La Fleur L, Backman M, Strell C, et al. Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation. Lung Cancer. 2021;155:10–9.
doi: 10.1016/j.lungcan.2021.02.028
pubmed: 33706022
Pellinen T, Paavolainen L, Martín-Bernabé A, Papatella Araujo R, Strell C, Mezheyeuski A, et al. Fibroblast subsets in non-small cell lung cancer: associations with survival, mutations, and immune features. J Natl Cancer Inst. 2023;115:71–82.
doi: 10.1093/jnci/djac178
pubmed: 36083003
Cords L, Engler S, Haberecker M, Rüschoff JH, Moch H, de Souza N, et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer. Cancer Cell. 2024;42:396–412.
doi: 10.1016/j.ccell.2023.12.021
pubmed: 38242124
pmcid: 10929690
Davidson S, Efremova M, Riedel A, Mahata B, Pramanik J, Huuhtanen J, et al. Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 2020;31:107628. https://doi.org/10.1016/j.celrep.2020.107628 .
doi: 10.1016/j.celrep.2020.107628
pubmed: 32433953
pmcid: 7242909
Xing X, Yang F, Huang Q, Guo H, Li J, Qiu M, et al. Decoding the multicellular ecosystem of lung adenocarcinoma manifested as pulmonary subsolid nodules by single-cell RNA sequencing. Sci Adv. 2021;7:eabd9738.
Merchant N, Nagaraju GP, Rajitha B, Lammata S, Jella KK, Buchwald ZS, et al. Matrix metalloproteinases: their functional role in lung cancer. Carcinogenesis. 2017;38:766–80.
doi: 10.1093/carcin/bgx063
pubmed: 28637319
Tang H, Chen J, Han X, Feng Y, Wang F. Upregulation of SPP1 is a marker for poor lung cancer prognosis and contributes to cancer progression and cisplatin resistance. Front Cell Dev Biol. 2021;9:1–9.