Broad misappropriation of developmental splicing profile by cancer in multiple organs

Abstract

Oncogenesis mimics key aspects of embryonic development. However, the underlying molecular determinants are not completely understood. Leveraging temporal transcriptomic data during development in multiple human organs, we demonstrate that the 'embryonic positive (EP)' alternative splicing events, specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. EP events are associated with key oncogenic processes and their reactivation predicts proliferation rates in cancer cell lines as well as patient survival. EP exons are significantly enriched for nitrosylation and transmembrane domains coordinately regulating splicing in multiple genes involved in intracellular transport and N-linked glycosylation respectively, known critical players in cancer. We infer critical splicing factors (CSF) potentially regulating these EP events and show that CSFs exhibit copy number amplifications in cancer and are upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs results in decreased EP splicing, further supporting their causal role. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of CSFs in brain and liver, which can be potentially targeted using FDA approved drugs. Our study provides the first comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest novel targets including splicing events, splicing factors, and transcription factors.