Developmental origins of cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We have three subprojects to report. 1. 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, are mutational hotspots and somatic drivers in multiple cancer types and upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs in cancer patients and shRNA knockdown in HepG2 cell line results in decreased EP splicing, 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. This works was deposited in BioRxiv and is currently under review. 2. In collaboration with Merlino lab@NCI we have analyzed the in-house single cell transcriptomics data of developing melanoblasts in mouse at 2 developmental timepoints - E11.5 and E15.5. We have identified several cellular states among the developing melanoblasts and show that some of the Schwann cell progenitor and Mesenchymal states are recapitulated in the melanoma metastasis. Through an extensive analysis of publicly available data we show that these states are associated with patient survival in human melanoma and are associated with vemurafenib and ICB resistance. This is very exciting development and we are currently starting to write the manuscript. 3. As a side project, we have also started analyzing the links between oncogenesis and three key homeostatic processes, namely, Stress response, Wound Healing, and Regeneration. We have compiled genes associated with these processes from original perturbation experiments in multiple species. We show that indeed known human cancer drivers highly overlap with these processes, are proximal to these processes in the protein-interaction network, and very interestingly, we show that based simply on the proximity from these processes in the protein interaction network, we can predict known cancer drivers from other genes. This work is close to finishing and we will start writing the manuscript in a couple of months. We have also contributed to a publication by Ruppin lab that perform a comparative analysis across multiple species, relating gene conservation and cancer risk, to identify cancer-resistance associated genes that may mediate human cancer risk.