Endocrine Abstracts

Glioblastoma (GBM; grade IV astrocytoma) is one of the most devastating endocrine-related cancer worldwide based on its locally aggressive behavior and because it cannot be cured by current therapies. Therefore, the identification of novel diagnostic and prognostic biomarkers, and especially efficient therapeutic targets is urgently needed. In this sense, defects in alternative splicing process are associated with poor survival and high aggressiveness in cancer, including GBM. Specifically, splicing factor SF3B1 (splicing-factor-3B-subunit-1), an essential and druggable component of spliceosome (machinery responsible for splicing process), has been identified as a key dysregulated factor in some endocrine-related cancer (e.g. prolactinomas and breast cancer); however, the oncogenic implication of SF3B1, its somatic mutations, and expression profile or its association with molecular features and clinical parameters have not been characterized in GBM, nor its putative therapeutic potential. Therefore, different human cohorts and dataset from different glioma mouse models were analyzed to determine the mutation frequency as well as the gene and protein expression levels between tumor and control samples of SF3B1. SF3B1 expression was also explored at the single cell level across all cell subpopulation and transcriptomic programs. The association of SF3B1 expression with relevant clinical data in different human cohorts was also analyzed. Moreover, different functional (proliferation/migration/tumorspheres-formation/ VEGF-secretion/apoptosis) and molecular/mechanistic (gene expression/signaling-pathways) assays were performed in different glioblastomas cell models (human primary-cultures and cell-lines) in response to SF3B1 blockade (using pladienolide B treatment). Additionally, tumor onset, formation and progression were monitored in response to SF3B1 blockade in a preclininal mouse model. Our data provide novel evidence demonstrating that SF3B1 is low-frequency mutated in human gliomas (1%) but widely overexpressed in glioblastoma compared with control samples from the different human cohorts and mouse models included in the present study, wherein SF3B1 levels are associated with key molecular and clinical features (e.g., overall survival, poor prognosis and/or drug-resistance). Remarkably, in vitro and in vivo blockade of SF3B1 activity with pladienolide B drastically altered multiple glioblastoma pathophysiological processes (i.e., reduction in proliferation, migration, tumorspheres-formation, VEGF-secretion, tumor initiation and increase in apoptosis) likely by suppressing AKT/mTOR/ß-catenin pathways, causing an imbalance of BCL2L1 splicing. Together, we highlight SF3B1 as a potential diagnostic and prognostic biomarker and an efficient pharmacological target in glioblastoma, offering a clinically relevant opportunity worth to be explored in humans.

Fundings: MINECO (PID2019-105564RB-I00), Junta de Andalucía (P20_00442, BIO-0139) and CIBERobn.