Grace Bushnell, PhD, Postdoctoral Research Fellow, University of Michigan
Despite the benefits of adjuvant therapy, patients with ER+ breast cancer face a constant risk of recurrence for the remainder of their life. A reservoir of disseminated tumor cells (DTCs) must exist that escape therapy, grow slowly or not at all, and can be reactivated. A major challenge to the understanding of these interactions is the lack of models of estrogen receptor positive dormancy in fully immunocompetent mice. We aim to address this by developing an immunocompetent model of breast cancer dormancy. We investigated five syngeneic murine breast cancer cell lines for long-term and short-term dormancy in vivo. We found three cell lines in which mice survive for >100d after intracardiac inoculation (compared to <20d for non-dormant cell lines). We further investigated the role of the immune system in these models by inoculating cells into mice with varying defects in adaptive or innate immunity. We found each cell line shows differential sensitivity to various immune compartment loss. The D2.0R cell line showed no requirement for dormancy on the adaptive immune system, however survival was significantly reduced in NSG mice compared to NODscid mice. To identify the cell type responsible, we depleted various immune cell populations and found natural killer (NK) cells were responsible for this survival difference. We next investigated the differential response of quiescent vs proliferative D2.0R cells to NK cells and found quiescent cells were resistant to NK cell killing compared to proliferative cells. We investigated the mechanism of this phenotypic difference via bulk RNAseq, single cell RNAseq, and Visium spatial gene expression analysis. We found the transcription factor Bach1 drives NK cell resistance through upregulation of MHC-I and downregulation of NKG2D ligand RAE1. Taken together these models provide a platform for the better understanding of the immune system role in maintaining breast cancer dormancy and identify a mechanism for quiescent tumor cell evasion of NK cell surveillance.
Dr. Grace Bushnell is currently a K99/R00 postdoctoral fellow with Max Wicha in the Biointerface Institute, Forbes Institute for Cancer Discovery, and Internal Medicine in the University of Michigan Medical School. She completed her Ph.D. in BME advised by Lonnie Shea at University of Michigan and completed her B.S. in BME with research mentorship from Phillip Messersmith at Northwestern University. Her doctoral research focused on engineering biomaterial implants to recruit, detect, and study metastatic tumor cells. Her postdoctoral research developedimmunocompetent models of breast cancer dormancy and defined the mechanism of metastatic latency. Her future research laboratory the Oncomaterials Research Group (ORG) will investigate breast cancer dormancy at the interface of cancer biology, biomaterials, and immunology.