The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Gastroenterology
Hiroki KobayashiSusan L Woods

Abstract

Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biologi...Continue Reading

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Citations

May 8, 2021·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Akitoshi HaraAtsushi Enomoto
Jun 12, 2021·Biomarker Research·Zimu WangYong Song
Sep 8, 2021·Nature Reviews. Clinical Oncology·Yang ChenRaghu Kalluri
Sep 23, 2021·Cancer Biotherapy & Radiopharmaceuticals·Jingwen LiuJianming Li

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