Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer.

Authors

Debasish Boral, Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX 77030, USA
S Ray Kenney, Division of Molecular Medicine, Department of Internal Medicine, The University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA
Dario Marchetti, Division of Molecular Medicine, Department of Internal Medicine, The University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA
Haowen N. Liu, Biochemistry lab, Complete Genomics Inc., San Jose, CA 95134, USA

Document Type

Article

Publication Date

6-19-2020

Abstract

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. To overcome these hurdles, we developed a new experimental model of clinical dormancy employing patient-isolated Circulating Tumor Cells (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 the knockdown of RICTOR, an essential component of mTORC2, and 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.

Recommended Citation

Boral D, Liu HN, Kenney SR, Marchetti D. Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer. Cancers (Basel). 2020 Jun 19;12(6):1626. doi: 10.3390/cancers12061626. PMID: 32575420; PMCID: PMC7352937.