Abstract:
A key feature of cancer development is the loss of gene regulatory programs that govern normal cellular identity; however, these disrupted regulatory landscapes, or epigenomic states, are not well understood. To study epigenomic state changes in the natural evolution of lung adenocarcinoma (LUAD), I utilized the well-established KrasG12D/+p53-/- (KP) murine model of LUAD progression. Using an optimized single-cell ATAC-sequencing approach with combinatorial indexing, I profiled the chromatin accessibility states of individual KP tumors, metastases, and normal lungs. Strikingly, we identified expansive epigenomic heterogeneity across cancer progression; yet, these cell states followed reproducible trajectories across individual tumors—suggesting conserved paths toward metastasis. We utilized computational tools to identify 11 discernable states across LUAD cancer progression characterized by transcription factor (TF) regulators and downstream regulated genes. These analyses led to the identification of a late-stage program associated with progressive RUNX2 activation and adverse survival in human patients. Together, these results demonstrated the utility of single-cell epigenomics to identify TF-driven regulatory programs as key biomarkers of cancer progression. My ongoing work leverages evolving epigenomic technologies in murine and organoid systems to understand the overarching mechanisms dictating altered chromatin state in cancer.

Speaker:
Lindsay M. LaFave is a cancer biologist with a long-standing interest in studying chromatin biology. Lindsay completed her B.S. in biochemistry at the University of Michigan in 2009. She received her Ph.D. in Cancer Biology at Gerstner Sloan Kettering Graduate School in New York City in 2015. Her graduate research in Ross Levine’s lab at Memorial Sloan Kettering Cancer Center focused on studying the role of mutated chromatin modifying proteins in hematopoietic malignancies. For her postdoctoral training, she continued to study epigenetic mechanisms of cancer progression, shifting her primary focus to solid tumors. Lindsay is a current Damon Runyon postdoctoral fellow in the labs of Tyler Jacks at MIT and Jason Buenrostro at Harvard University. Her work leverages murine modeling and single-cell epigenomic technologies to understand cell state changes that occur during cancer progression in lung adenocarcinoma. During her postdoctoral training, Lindsay identified a diverse repertoire of gene regulatory changes important in cancer progression that were associated with altered cellular identity and the emergence of pre-metastatic gene programs. Her independent research group will utilize evolving epigenomic technologies and cancer models to dissect chromatin-mediated mechanisms driving lung cancer.