Tumor recurrence is the primary cause of cancer-related mortality. Recurrent tumors arise from residual cancer cells surviving treatment of the primary tumor. It remains unclear whether residual tumor cells are quiescent, or whether they are proliferative but tumor recurrence is limited by a countervailing level of cell death, due to insufficient vascularization or an inhospitable microenvironment. Using inducible models for HER2/neu and Wnt1 mammary tumorigenesis, we found that residual tumor cells surviving oncogene inhibition are quiescent, and reside in a desmoplastic and well-vascularized microenvironment. We confirmed these results by performing gene expression analysis on residual tumor cells, primary tumor cells, recurrent tumor cells, and stromal cells. Gene ontology analysis identified dramatic downregulation of gene clusters associated with proliferation in dormant residual tumor cells compared to all other cell types. Genes we identified as up- or downregulated in dormant residual disease were identified in other models of dormancy, suggesting generalizable mechanisms underpinning dormancy in different contexts. Dormancy-specific changes in additional genes further suggest a role for both EMT and stem cell-related signaling in dormant residual disease which survives targeted therapy. Finally, we demonstrated quiescent residual disease in a xenograft model of breast cancer treated with clinically relevant targeted therapies. In summation, these results suggest both that residual disease may exhibit cellular dormancy following targeted therapy, and that some mechanisms regulating cellular quiescence may be similar across different contexts.
Citation Format: Jason Ruth, Dhruv Pant, Blaine Keister, Christopher Sterner, Lewis Chodosh. Cellular dormancy in residual disease following oncogene inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2014-4985