Transcriptomics

Biography

Biography: Wei Zhang

Abstract

Recent high throughput interrogations of cancer landscape through programs such as The Cancer Genome Atlas (TCGA) have gained deeper understanding of cancer as a disease of heterogeneity of different stages of cell fate evolution and dedifferentiation. Epithelial tumors often exhibit mesenchymal features as a result of epithelial to mesenchymal transition (EMT), a process that can be driven by both genetic and epigenetic alterations in a form of network regulation. In ovarian cancer, loss of epithelial features and gain of a mesenchymal phenotype is associated with more aggressive tumor features. We performed an integrated genomic analysis, which revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer from TCGA and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 inhibited EMT by targeting SNAI2, a transcriptional repressor of E-cadherin, as well as mesenchymal regulators vimentin and N-cadherin. MiR-506 also induced senescence by blocking CDK4/6-FoxM1 axis. We used our well-characterized nanoparticle platforms for systemic delivery of miR-506 in orthotopic OvCa mouse models and found such delivery to be highly effective for reduced tumor growth. Interestingly, mesenchymal tumors such as leiomyosarcoma and synovial sarcoma often exhibit epithelial features in a process of mesenchymal to epithelial transition (MET). MET in sarcoma is associated with improved prognosis. Therefore, reprogramming is an intrinsic hallmark of cancer. Understanding of this reprogramming promises to lead to intervention that program cancer into an attractor stage that is more similar to normal cells or a stage that leads to irreversible cell death.