Get started
Work

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK / ERK ‐dependent colorectal cancer

Year: 2023
Type: article
Abstract: The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context-dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP-rich environment based on curation of two publicly available RNA-sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA-approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders to this regimen.
DOI: 10.1111/cas.15882
Authors: Shota Shimizu, Jumpei Kondo, Kunishige Onuma, Roberto Coppo, Kasumi Ota, Mayumi Kamada, Yohei Harada, Yoshihisa Tanaka, Mai Adachi Nakazawa, Yoshinori Tamada, Yasushi Okuno, Kenji Kawada, Kazutaka Obama, Robert J. Coffey, Yoshiyuki Fujiwara, Masahiro Inoue
Institutions: Kyoto University, Tottori University, Osaka International Cancer Institute, Vanderbilt University Medical Center, The University of Osaka, RIKEN Center for Computational Science, Hirosaki University
Language: English
Open Access status: gold
Estimated APC paid: $2,600
Funders: Takeda Science Foundation, Japan Agency for Medical Research and Development, Taiho Pharmaceutical, Cabinet Office, Government of Japan, Chugai Pharmaceutical, Japan Society for the Promotion of Science, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Functional single cell analysis and drug screening in tumor organoids to target slow-growing cells, G2239105477, G2243691917, The mechanisms of BMP-EGFR cross talk in colorectal organoids, G4965266176, Systems pathology approach using deep learning to understand the effect of environmental exposure on the pathogenesis of common diseases, Mechanisms of the immune evasion through polarity switching of the colorectal cancer clusters, Roe of polarity switching of cancer cell clusters in metastasis, Molecular and Cellular Basis for Digestive Diseases, Early to Late Events in Colorectal Neoplasia: Basic Biology to Clinical Implementation, Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
OpenAlex ID: W4381948313
FWCI: 1.038
Cites: 43
Cited by: 12
Related to: 10