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

Hiroki Kobayashi, Krystyna A. Gieniec, Josephine A. Wright, Tongtong Wang, Naoya Asai, Yasuyuki Mizutani, Tadashi Lida, Ryota Ando, Nobumi Suzuki, Tamsin R.M. Lannagan, Jia Q. Ng, Akitoshi Hara, Yukihiro Shiraki, Shinji Mii, Mari Ichinose, Laura Vrbanac, Matthew J. Lawrence, Tarik Sammour, Kay Uehara, Gareth DaviesLeszek Lisowski, Ian E. Alexander, Yoku Hayakawa, Lisa M. Butler, Andrew C.W. Zannettino, M. Omar Din, Jeff Hasty, Alastair D. Burt, Simon J. Leedham, Anil K. Rustgi, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Daniel L. Worthley, Susan L. Woods

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: 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. Methods: 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. Results: 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 biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)–mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Original languageEnglish
Pages (from-to)1224-1239.e30
JournalGastroenterology
Volume160
Issue number4
DOIs
Publication statusPublished - 03-2021

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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