A tumor-associated splice-isoform of MAP2K7 drives dedifferentiation in MBNL1-low cancers via JNK activation
Menée à l'aide de lignées cellulaires, d'un modèle murin, d'échantillons tumoraux, d'échantillons tissulaires adjacents et de données du projet "The Cancer Genome Atlas", cette étude met en évidence un mécanisme par lequel une isoforme d'épissage de la kinase MAP2K7, via l'activation de la kinase JNK, induit la dédifférenciation des cellules cancéreuses exprimant faiblement la protéine régulatrice MBNL1, puis identifie des biomarqueurs permettant de prédire la susceptibilité des cellules cancéreuses à l'inhibition de JNK
Targeting stem-like cells in cancer is critical to overcoming resistance and relapse post chemotherapy or immunotherapy. We elucidate an alternative-splicing driven mechanism of cancer dedifferentiation and define a molecular context wherein stem-like tumor cells show enhanced susceptibility to JNK inhibition. MBNL1 and MAP2K7∆exon2 can prognosticate patients for JNK inhibition that can render stem-like tumor cells susceptible to therapy. 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 MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 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 MBNL1-low cancers and embryonic stem cells including a MAP2K7∆exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7∆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.