Characterization of an RNA binding protein interactome reveals the targetable post-transcriptional landscape of MYC-amplified medulloblastoma

Abstract

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identified binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry

“…The primary structural elements of Musashi proteins comprise a pair of tandem RRM domains (RRM1 and RRM2) [54], which they use to bind the 3' UTR region of specific target mRNAs and thus regulate both mRNA stability and translation of the proteins these mRNAs encode. Many of these proteins regulated by MSI1/MSI2 are involved in key signaling pathways that play essential roles in development and are abnormally activated in oncogenesis, such as maintenance of stem cell capacity and promotion of epithelial-mesenchymal transition (NUMB/NOTCH, PTEN/mTOR, TGFβ/SMAD3, MYC) [55,56]; it is thus unsurprising that elevated expression of MSI1/MSI2 has been observed in a broad spectrum of cancers [57][58][59][60][61][62][63][64]. In addition to their roles driving cancer initiation and progression, MSI1/MSI2 have also been implicated in conferring resistance to radiotherapy [65][66][67][68][69], chemotherapy [68,[70][71][72], and targeted therapies [73,74].…”