Molecular Interplay between Dormant 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. To overcome these hurdles, we developed a new experimental model of clinical dormancy e...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1626 |
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| author | Debasish Boral Haowen N. Liu S. Ray Kenney Dario Marchetti |
| author_facet | Debasish Boral Haowen N. Liu S. Ray Kenney Dario Marchetti |
| author_sort | Debasish Boral |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:02:30Z |
| format | Article |
| id | doaj.art-b2cb39087bcf443cb74f8232231ef3ba |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:02:30Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b2cb39087bcf443cb74f8232231ef3ba2023-11-20T04:20:40ZengMDPI AGCancers2072-66942020-06-01126162610.3390/cancers12061626Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast CancerDebasish Boral0Haowen N. Liu1S. Ray Kenney2Dario Marchetti3Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX 77030, USABiochemistry lab, Complete Genomics Inc., San Jose, CA 95134, USADivision of Molecular Medicine, Department of Internal Medicine, The University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USADivision of Molecular Medicine, Department of Internal Medicine, The University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USADespite 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.https://www.mdpi.com/2072-6694/12/6/1626Bone Marrow-Resident Breast Cancer Cells (BMRCs)Circulating Tumor Cells (CTCs)bone marrow (BM)CTC-derived xenograft (CDX)mTOR pathwaymTORC1/mTORC2 signaling |
| spellingShingle | Debasish Boral Haowen N. Liu S. Ray Kenney Dario Marchetti Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer Cancers Bone Marrow-Resident Breast Cancer Cells (BMRCs) Circulating Tumor Cells (CTCs) bone marrow (BM) CTC-derived xenograft (CDX) mTOR pathway mTORC1/mTORC2 signaling |
| title | Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer |
| title_full | Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer |
| title_fullStr | Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer |
| title_full_unstemmed | Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer |
| title_short | Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer |
| title_sort | molecular interplay between dormant bone marrow resident cells bmrcs and ctcs in breast cancer |
| topic | Bone Marrow-Resident Breast Cancer Cells (BMRCs) Circulating Tumor Cells (CTCs) bone marrow (BM) CTC-derived xenograft (CDX) mTOR pathway mTORC1/mTORC2 signaling |
| url | https://www.mdpi.com/2072-6694/12/6/1626 |
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