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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.

SUBMITTER: McAndrews KM

PROVIDER: S-EPMC9150816 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

McAndrews Kathleen M KM Vázquez-Arreguín Karina K Kwak Changsoo C Sugimoto Hikaru H Zheng Xiaofeng X Li Bingrui B Kirtley Michelle L ML LeBleu Valerie S VS Kalluri Raghu R

Oncogene 20210609 26

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 ...[more]

PMID: 34108617

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Project description:Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.

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

Publications

αSMA<sup>+</sup> fibroblasts suppress Lgr5<sup>+</sup> cancer stem cells and restrain colorectal cancer progression.

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