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αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression

Abstract

The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA+ CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA+ CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA+ CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5+ cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3+ regulatory T cells and suppression of CD8+ T cells. This study demonstrates that αSMA+ CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5+ CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.

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Fig. 1: Depletion of αSMA+ CAFs leads to increased tumor invasion and decreased survival in CRC model.
Fig. 2: Loss of αSMA+ CAFs increases rates of local invasion.
Fig. 3: αSMA+ CAF-depleted CRC tumors display an enhanced CSC phenotype.
Fig. 4: Depletion of αSMA+ myofibroblasts induces an immunosuppressive phenotype.

Data availability

The source data for all the figures in the manuscript can be downloaded at: https://doi.org/10.17632/w8kmnbpyfw.1. Raw and processed RNA-sequencing data are deposited in the Gene Expression Omnibus database (accession number GSE164300).

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Acknowledgements

This study was supported by research funds provided by the MD Anderson Cancer Center. KV-A is supported by Ruth L. Kirschstein National Research Service Award 5T32CA186892. We thank Dr. Ronald DePinho for providing the iKAP mouse model and for insightful comments on the manuscript. We thank Dr. Adam Boutin for his generous help with the project, Dr. Krishnan Mahadevan for advice on proliferative index determination, and Patience Kelly for assistance with slide scanning and staining. The Advanced Technology Genomics Core is supported by the core grant CA016672(ATCG).

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CK, KV-A, KMM, XZ, and MLK performed experiments and analyzed data. HS assisted with mouse experiments. BL analyzed the global transcriptomic data. KV-A, CK, KMM, and VSL prepared figures. KV-A, CK, KMM, VSL, and RK wrote and edited the manuscript. RK conceptualized and supervised the study.

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Correspondence to Raghu Kalluri.

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McAndrews, K.M., Vázquez-Arreguín, K., Kwak, C. et al. αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression. Oncogene 40, 4440–4452 (2021). https://doi.org/10.1038/s41388-021-01866-7

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