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LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

ABSTRACT: Tumors generate various forces during growth and progression, which, in turn, promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile force. However, the role of these forces in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrate that the Hippo pathway kinases LATS1/2 in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell–cell interactions. In murine breast cancer 4T1 spheroids, deletion of LATS1/2 dampens force generation and disrupts the reorganization of surrounding collagen matrix. The LATS1/2-mediated mechanical forces of the tumor are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of the collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation, but also suggest potential strategies for targeting the Hippo pathway in cancer therapy from the mechanobiological perspective, offering new avenues in the fight against cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE282581 | GEO | 2025/05/22

REPOSITORIES: GEO

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Project description:Background: Post-transcriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. Modifications to m6A are dynamic and reversible in cancer cells and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of m6A methylation in the Hippo pathway, a key pathway involved in cell proliferation and metabolism. Methods: First, a combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal the map of m6A modifications in breast cancer tissues and cells. Secondly, we identified the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells by performing RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis. The expression and biological functions of METTL3 and YTHDF2 were confirmed in breast cancer cell lines in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway could be affected by m6A regulation of LATS1 in breast cancer cells. Results: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. Conclusions: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

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LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

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