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Unfortunately, breast cancer can recur in patients upwards of 25 years after an initial diagnosis and “cure”. It was once thought that recurrence occurred within patients that harbored dormant breast disseminated tumor cells (DTCs) in distant organs that were not present in patients that did not recur. Interestingly, a significant percent of patients harbor DTCs, yet many do not recur, raising the critical question, what differentiates patients that experience a recurrence versus those who live with dormant DTCs for the rest of their lives? It is likely the answer lies in both cell intrinsic as well as extrinsic factors. Nevertheless, the extreme rarity of dormant DTCs has been the major obstacle to their study. To overcome this challenge, we developed an efficient system to isolate and study rare dormant tumor cells from metastatic organs. Using this system and single cell RNA-sequencing (scRNA-seq), we identified a group of genes differentially expressed in dormant breast cancer cells present in both bone and lung. While modulation of these genes individually had no impact on the metastatic behavior of breast cancer cells, we found that as a group, these genes predicted the dormancy phenotype in murine breast cancer models. Importantly, expression of these genes in primary human breast cancer tumors correlated with disease-free survival, suggesting these genes have predictive value in determining which patients are likely to recur. Moreover, we explored extrinsic mechanisms that impact dormancy and found that the chemotherapy reagent doxorubicin (Doxo) drastically changed the microenvironment in vivo, which allowed dormant breast cancer cells to grow robustly within the visceral fat and this was further exacerbated by a high fat diet. Further, we found that Doxo treatment induces significant adipose tissue dystrophy and macrophage infiltration, which may contribute to dormant metastatic outgrowth. Our study provides novel insight into breast cancer dormancy, and also reveals microenvironmental changes that impact dormant breast cancer cell outgrowth. Citation Format: Qihao Ren, Weng Hua Khoo, Jiayu Ye, Douglas V. Faget, Peter I. Croucher, Sheila A. Stewart. Investigating the intrinsic and extrinsic factors regulating breast cancer dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2450. |
