Deciphering molecular mechanisms of Epithelial Plasticity

Project Summary/Abstract Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasizing to distant organs. EMT is a common feature associated with tumor progression and is thought to be critical to cancer cell dissemination in some tumors. Despite significant evidence that EMT directly contributes to tumor progression, several studies have suggested EMT is not required for the metastatic spread of PDA and breast cancer. For example, most metastatic lesions are known to exhibit epithelial features, an observation that seems to be at odds with EMT as a prerequisite for metastasis. As such, the importance of EMT in cancer biology has been questioned. I hypothesize that the chronic activation of an EMT program within a tumor may depend on paracrine signals within the tumor microenvironment, dictating whether the tumor cells undergo EMT or MET. Because these cells exist in a plastic state, it is possible that these tumor cells readily revert their phenotype based on a microenvironment-specific context and factors. Additionally, current in vivo lineage-tracing technology has not settled the debate between the importance of collective migration and/or EMT for metastatic dissemination. During my postdoctoral research, I aim to investigate this hypothesis in two aims: 1) Decipher genetic changes required for cellular plasticity using a novel patient-derived organoid lineage tracing model, live-imaging and single cell analyses. 2) Investigate extracellular cues for cellular plasticity and EMT by evaluating the role of the immune system in EMT and metastasis. These aims will allow the field to better understand epithelial plasticity in an oncogene- and tissue-specific manner. Understanding this process will aid in the development of effective metastatic cancer therapies and will direct future research directions in metastasis.