Twist Maintains Stemness in Latent Breast Cancer Metastases Through a Novel Non DNA-Binding Function Targetable With Small Molecules
Abstract
The Twist induced EMT program in a primary tumor is required for proliferation, migration, invasion and colonization of distant organs. Once cells are disseminated, a genetically and biochemically separate domain of Twist: the WR domain functions to maintain the metastatic tumor cells in a quiescent (possibly pluripotent) state by rendering the cells resistant to differentiation inducing signals, similar to what happens during development. The COOH-terminal Twist WR domain is required for binding directly to lineage specific transcription factors and inhibiting their function. The goals of this project are to define how Twist and the WR domain function to maintain the undifferentiated state in these latent disseminated cells. Progress in this first year of support includes: 1. Definition of the spectrum of proteins bound by to endogenous, cell derived Twist in a breast cancer cell line undergoing EMT. 2. Reconstitution of this complex with purified recombinant Twist -E47-Snail and Sox9 proteins. Consistent with our original hypothesis and AIMS, the complex contains DNA binding proteins which do not bind their sites when bound to the WR domain. Our Goals and SOW remain unchanged.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 30, 2018
- Accession Number
- AD1097119
Entities
People
- Frank Iii J. Rauscher
Organizations
- Wistar Institute