Broad misappropriation of developmental splicing profile by cancer in multiple organs

Arashdeep Singh (), Arati Rajeevan, Vishaka Gopalan, Piyush Agrawal, Chi-Ping Day and Sridhar Hannenhalli ()
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Arashdeep Singh: National Cancer Institute, National Institutes of Health
Arati Rajeevan: National Cancer Institute, National Institutes of Health
Vishaka Gopalan: National Cancer Institute, National Institutes of Health
Piyush Agrawal: National Cancer Institute, National Institutes of Health
Chi-Ping Day: National Institutes of Health
Sridhar Hannenhalli: National Cancer Institute, National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Oncogenesis mimics key aspects of embryonic development. However, the underlying mechanisms are incompletely understood. Here, we demonstrate that the splicing events specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. Such events are associated with key oncogenic processes and predict proliferation rates in cancer cell lines as well as patient survival. Such events preferentially target nitrosylation and transmembrane-region domains, whose coordinated splicing in multiple genes respectively affect intracellular transport and N-linked glycosylation. We infer critical splicing factors potentially regulating embryonic splicing events and show that such factors are potential oncogenic drivers and are upregulated specifically in malignant cells. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of critical splicing factors in brain and liver. Our study provides a comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest anti-cancer targets including splicing events, and their upstream splicing and transcriptional regulators.

Date: 2022
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DOI: 10.1038/s41467-022-35322-1

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