Abstract PO001: Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer

Despite widespread knowledge that bone marrow-resident breast cancer cells (BMRCs) affect tumor progression, signaling mechanisms of BMRCs implicated in maintaining long-term dormancy have not been characterized. Further, there is no model of clinical dormancy that can comprehensively emulate the entire spectrum of heterogeneous clones of Circulating Tumor Cells (CTCs) present in cancer patients. To overcome these hurdles, we developed a new experimental model of clinical dormancy employing patient-isolated de novo CTCs and their injection in xenografts with subsequent tumor monitoring and CTC characterization (ex vivo CTCs). We hypothesized that significant distinctions exist between signaling pathways of bone marrow-homing vs metastasis-competent CTCs upon transplantation in xenografts. Comparative transcriptomic analyses of ex vivo vs de novo CTCs identified increased mTOR signaling – a critical pathway frequently dysregulated in breast cancer and implicated in cell survival and dormancy – with contrasting actions by its two complementary arms (mTORC2/mTORC1). Heightened mTORC2 downstream targets augmented quiescent CTCs (Ki67-/RBL2+ cells) in paired breast cancer tissues, along with high mTORC2 activity in solitary BMRCs and tissue-resident CTCs. Further, shRNA mediated knockdown of RICTOR, an essential component of mTORC2, augmented Ki67/PCNA biomarker expression and proliferation. Collectively, these findings suggest that the balance between mTORC1 vs mTORC2 signaling regulates CTC-associated mitotic and/or dormancy characteristics. Further elucidation of mTOR-mediated CTC dormancy will provide novel strategies for therapeutic interventions in patients having early-event metastatic seeding but yet to develop clinically-detectable overt metastasis. Citation Format: Debasish Boral, Shelby R. Kenney, Haowen N. Liu, Dario Marchetti. Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO001.