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A Wnt-induced phenotypic switch in cancer-associated fibroblasts inhibits EMT in colorectal cancer

ABSTRACT: Tumor progression is recognized as a result of an evolving crosstalk between tumor cells and their surrounding non-transformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer (CRC), it remains unclear whether activity in the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent tumor organoids that secrete the Wnt antagonist Sfrp1. Upon subcutaneous transplantation into immuno-competent as well as -deficient mice, we observed strong reduction of tumor growth. Histological and transcriptomic analyses revealed that Sfrp1 induces an EMT (epithelial-mesenchymal transition) phenotype in tumor cells without affecting tumor-intrinsic Wnt signaling, suggesting involvement of non-immune stromal cells. Indeed, blockage of canonical signaling using Sfrp1, Dkk1, or fibroblast-specific genetic ablation of β-catenin strongly decreased the number of cancer-associated myofibroblasts (myCAFs). Interestingly, we found that the Wnt activity in CAFs is linked with distinct subtypes, where low and high levels induce an inflammatory-like CAF (iCAF) subtype or contractile myCAFs, respectively. Co-culture of tumor organoids with iCAFs resulted in massive upregulation of EMT markers, while myCAFs reverted this phenotype. In summary, we show that tumor growth and malignancy are differentially regulated via district fibroblast subtypes under the influence of juxtacrine Wnt signals.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE155364 | GEO | 2020/10/15

REPOSITORIES: GEO

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Myelodysplastic syndrome marrow stroma shows widespread aberrant hypermethylation that is abrogated by treatment with DNMT inhibitors

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