Determining the Molecular Basis and Therapeutic Potential of Hyperactive Stem Cell Programs in Colorectal Cancer
Abstract
Impaired differentiation is a hallmark of CRC and the functional mediators have yet to be elucidated. To define factors that block differentiation, we investigated downstream targets of SOX9 in Aim 1. We found that SOX9 activates PROM1 via an intronic enhancer, and that PROM1 is also capable of blocking differentiation in CRC; these findings were published in Gastroenterology. We also used RIME to identify essential molecular co-factors of SOX9, which we are now in the process of validating. In Aim 2, we designed an endogenous knock-in reporter system that measures stem cell activity and differentiation activity in CRC. Using this new platform, we performed a focused library genetic and small-scale drug screen targeting epigenetic regulators. We found key epigenetic regulators of differentiation in CRC and identified an epigenetic inhibitor that promotes differentiation; mechanism of action is now being investigated. In Aim 3, we performed a molecular study that showed truncating SOX9 heterozygous alterations lack canonical or dominant-negative function in CRC, which was published in Gastro Hep Advances. We also developed a genetically engineered mouse model to study Sox9 function in vivo, which led a manuscript currently under review. Collectively, these experiments will provide critical insight into CRC pathogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1192065
Entities
People
- Nilay S Sethi
Organizations
- Dana–Farber Cancer Institute