Ashley Laughney, Ph.D.
BME Faculty Candidate and Guest Speaker
Memorial Sloan Kettering Cancer Center

“Dissecting tumor cell plasticity and population interactions supporting metastasis using single cell genomics”

Abstract:

Disseminated tumor cells can give rise to metastasis months to years after detection and treatment of the primary tumor. The cellular mechanisms underlying delayed metastasis are poorly understood. Here we employ single-cell RNA sequencing to transcriptionally profile >80,000 cancer cells and infiltrating immune cells from primary and metastatic patient lung adenocarcinomas and in mouse models of metastasis-initiation. We show that primary tumors are replete with metastasis-initiating cells and demonstrate a striking level of developmental plasticity that is constrained to the SOX9 (distal) lineage in patient metastases. I recapitulated these findings in a mouse model of lung cancer metastasis, where I further demonstrate that growth-restricted (i.e. quiescent/dormant) MetSC conversely persist in a state of differentiation down the Sox2 proximal airway lineage. Using fluorescence lineage-tracing techniques, we show that these quiescent cells are monoclonal and retain metastatic stem-cell properties. This was in contrast to more aggressive metastatic derivatives that showed evidence of polyclonal seeding from the orthotopic site. Strikingly, depletion of Natural Killer (NK) cells allowed escape of cells that recapitulate both proximal and distal lung lineages; demonstrating that developmental plasticity during the invasion-metastasis cascade undergoes NK-cell mediated pruning. How tumor cells, either intrinsically or through adaptation, exploit such phenotypic plasticity and context-dependent cell-cell interactions for metastatic progression will remain the focus of my independent research program.