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Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.

ABSTRACT: Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.

SUBMITTER: Bota-Rabassedas N

PROVIDER: S-EPMC8142261 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.

Bota-Rabassedas Neus N Banerjee Priyam P Niu Yichi Y Cao Wenjian W Luo Jiayi J Xi Yuanxin Y Tan Xiaochao X Sheng Kuanwei K Ahn Young-Ho YH Lee Sieun S Parra Edwin Roger ER Rodriguez-Canales Jaime J Albritton Jacob J Weiger Michael M Liu Xin X Guo Hou-Fu HF Yu Jiang J Rodriguez B Leticia BL Firestone Joshua J A JJA Mino Barbara B Creighton Chad J CJ Solis Luisa M LM Villalobos Pamela P Raso Maria Gabriela MG Sazer Daniel W DW Gibbons Don L DL Russell William K WK Longmore Gregory D GD Wistuba Ignacio I II Wang Jing J Chapman Harold A HA Miller Jordan S JS Zong Chenghang C Kurie Jonathan M JM

Cell reports 20210401 3

Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory pr ...[more]

PMID: 33882319

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Project description:BackgroundCancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer.MethodsMurine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (αSMA), fibroblast activation protein alpha (FAPα), platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed.ResultsWe have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5-6 main CAF populations and numerous minor ones based on the analysis of αSMA, FAPα, PDGFRα, PDGFRβ, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFRα+ fibroblasts in healthy mammary tissue to predominantly PDGFRβ+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAPα+ CAFs in abundance.ConclusionWe demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations.

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Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.

Publications

Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.

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