A tumor-associated splice-isoform of MAP2K7 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 surveyedMBNL1expression in matched tumor/normal pairs across The Cancer Genome Atlas and found thatMBNL1was down-regulated in several common cancers. Down-regulation ofMBNL1predicted 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 betweenMBNL1-low cancers and embryonic stem cells including aMAP2K7∆exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversingMAP2K7∆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.

Tumorigenic de-differentiation: the alternative splicing way

“…presence of MAP2K7 ∆exon2 isoform in MBNL1- low cancers with high stem/progenitor-like properties ( Figure 1 ). 2 Our findings have important clinical implications. Biopsies from cancer patients can be assayed for MBNL 1 and MAP2K7 ∆exon2 isoform expression as patients with low MBNL1 and high MAP2K 7∆exon2 would be likely to benefit from JNK inhibition.…”

“…Muscleblind-like-1 (MBNL1) is an RNA binding protein that functions as a master-regulator of RNA-processing. It regulates alternative splicing, 1 , 2 alternative polyadenylation, 3 transcript localization 4 and transcript stability. 5 , 6 MBNL1 stabilizes or destabilizes key transcripts involved in metastasis to suppress metastasis in breast and colorectal cancers.…”

“…In RNA-seq data from breast and stomach cancer patients from the cancer genome atlas (TCGA), low MBNL1 expression levels correlated to increased expression of stemness gene signatures ( Figure 1 ). 2 It is hypothesized that a cancer stem-like cell may arise either by malignant transformation of normal tissue-specific stem/progenitor cells or via re-programming of mature somatic cells. Our data highlights a role of MBNL1 in tumorigenic de-differentiation of cells by re-wiring alternative splicing.…”

“…Our data highlights a role of MBNL1 in tumorigenic de-differentiation of cells by re-wiring alternative splicing. 2 It is important to note that stem-like features of cancer cells are central to tumor heterogeneity, cancer initiation, metastasis and relapse.

Figure 1.

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“…We further discovered that this MBNL1- MAP2K7 ∆exon2 mediated tumor de-differentiation is reversible by JNK inhibition ( Figure 1 ). 2 …”