Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer
1
Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX 77030, USA
2
Biochemistry lab, Complete Genomics Inc., San Jose, CA 95134, USA
3
Division of Molecular Medicine, Department of Internal Medicine, The University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1626; https://doi.org/10.3390/cancers12061626
Received: 19 May 2020
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Revised: 8 June 2020
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Accepted: 12 June 2020
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Published: 19 June 2020
(This article belongs to the Special Issue Liquid Biopsy: Latest Advances and Future Challenges)
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.
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Keywords:
Bone Marrow-Resident Breast Cancer Cells (BMRCs); Circulating Tumor Cells (CTCs); bone marrow (BM); CTC-derived xenograft (CDX); mTOR pathway; mTORC1/mTORC2 signaling; RICTOR; CTC-associated dormancy
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MDPI and ACS Style
Boral, D.; Liu, H.N.; Kenney, S.R.; Marchetti, D. Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer. Cancers 2020, 12, 1626. https://doi.org/10.3390/cancers12061626
AMA Style
Boral D, Liu HN, Kenney SR, Marchetti D. Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer. Cancers. 2020; 12(6):1626. https://doi.org/10.3390/cancers12061626
Chicago/Turabian StyleBoral, Debasish, Haowen N. Liu, S. R. Kenney, and Dario Marchetti. 2020. "Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer" Cancers 12, no. 6: 1626. https://doi.org/10.3390/cancers12061626
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