A tumor-associated splice-isoform of <i>MAP2K7</i> drives dedifferentiation in MBNL1-low cancers via JNK activation.

Abstract

Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed <i>MBNL1</i> expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that <i>MBNL1</i> was down-regulated in several common cancers. Down-regulation of <i>MBNL1</i> predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between <i>MBNL1</i>-low cancers and embryonic stem cells including a <i>MAP2K7∆</i>exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing <i>MAP2K7</i>∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.