Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer
Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer
复制标题
DOI：
10.1101/2022.11.01.514643
复制
发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Shota Shimizu;J. Kondo;K. Onuma;Kasumi Ota;M. Kamada;Yohei Harada;Yoshihisa Tanaka;M. Nakazawa;Y. Tamada;Yasushi Okuno;K. Kawada;K. Obama;R. Coffey;Y. Fujiwara;Masahiro Inoue
中科院分区：
文献类型：
--
作者：
Shota Shimizu;J. Kondo;K. Onuma;Kasumi Ota;M. Kamada;Yohei Harada;Yoshihisa Tanaka;M. Nakazawa;Y. Tamada;Yasushi Okuno;K. Kawada;K. Obama;R. Coffey;Y. Fujiwara;Masahiro Inoue
骨形态发生蛋白(BMP)途径促进正常大肠上皮细胞分化和诱导细胞凋亡。然而，BMP途径在结直肠癌(CRC)中的作用存在争议；根据研究，它可能是促进肿瘤的，也可能是抑制肿瘤的。在本研究中，基于RNA测序数据库的分析，我们发现CRC细胞存在于BMP丰富的环境中。在某些结直肠癌病例中，使用特定的BMP抑制剂LDN193189抑制BMP可抑制有机体的生长。经LDN193189处理的CRC有机物显示表皮生长因子受体减少，这至少部分是由富含亮氨酸的重复序列和免疫球蛋白样域蛋白1(LRIG1)诱导的蛋白质降解所致。在来自18个不同患者的结直肠癌类有机物中，通过抑制BMP抑制类有机物生长与诱导LRIG1基因表达有关。值得注意的是，LRIG1在有机物中的敲除减弱了LDN193189的生长抑制作用。此外，LDN192189与FDA批准的MEK抑制剂曲美替尼同时治疗，在体内和体外对结直肠癌有机化合物的异种移植瘤治疗都产生了联合作用，这些有机化合物容易受到LDN193189的生长抑制。综上所述，同时抑制BMP和MEK可能是结直肠癌治疗的一种新的选择，使用患者衍生的有机化合物评估BMP抑制体外生长抑制和LRIG1诱导可以为预测潜在的应答者提供功能生物标志物。
The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, the effect of the BMP pathway in colorectal cancer (CRC) is controversial; it can either be tumor promoting or tumor suppressing, depending on the study. In this study, we found that CRC cells reside in a BMP-rich environment based on RNA-sequencing database analysis. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of organoids in some CRC cases. CRC organoids treated with LDN193189 exhibited a decrease in epidermal growth factor receptor, which was, at least in part, mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1). Among CRC organoid panels from 18 different patients, suppression of organoid growth by BMP inhibition correlated with the induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, simultaneous treatment with LDN192189 and trametinib, an FDA-approved MEK inhibitor, resulted in a combination effect in both in vivo and in vitro xenograft tumor treatment in CRC organoids, which are susceptible to growth suppression by LDN193189. Taken together, the simultaneous inhibition of BMP and MEK can 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.