Mbnl1 Regulated Alternative Splicing Of Map2k7 Promotes De-Differentiation Of Cancer Cells By Activating Jnk

Therapeutic targeting of cancer stem cells (CSCs) is key to relapse-free, lasting response to cancer treatment. Several strategies against CSCs are currently in various stages of clinical development. However, there is need for additional targets. Here, we demonstrate that MBNL1, an RNA binding protein, is a suppressor of cancer-stemness. RNAi mediated down-regulation of MBNL1 promotes tumor-initiation, self-renewal, migration and invasion by up-regulating CSC-specific splice-isoforms. Particularly, the up-regulation of MAP2K7Δexon2 splice-isoform activates JNK signaling and establishes a feedback loop that promotes cancer-stemness. Pharmacological inhibition of JNK reverses CSC phenotypes in MBNL1low/MAP2K7Δexon2high CSC-like cells and these cells also show enhanced susceptibility to JNK inhibition. Remarkably, MBNL1 is down-regulated and MAP2K7Δexon2 splice-isoform is up-regulated in several cancer types. Down-regulation of MBNL1 is correlated with poor survival in gastric, lung and breast adenocarcinoma. In triple negative breast cancer, which is a highly aggressive disease characterised by enrichment of CSC-like cells, low MBNL1 correlates with poor relapse-free and distant metastasis-free survival. Our work shows, low MBNL1 and consequently high MAP2K7Δexon2 expression, is a biomarker for cancer stemness, high JNK activity and enhanced susceptibility to JNK inhibition. Hence, we have identified a novel alternative splicing driven mechanism of cancer cell de-differentiation and have identified biomarkers that can prognosticate patients for JNKi as a strategy to target CSCs. Citation Format: Debleena Ray. MBNL1 regulated alternative splicing of MAP2K7 promotes de-differentiation of cancer cells by activating JNK [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3778.