The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease.

Autor: Bishop RT; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Miller AK; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Froid M; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.; The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA., Nerlakanti N; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.; The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA., Li T; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Frieling JS; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Nasr MM; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.; The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA., Nyman KJ; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.; The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA., Sudalagunta PR; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Canevarolo RR; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Silva AS; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Shain KH; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Lynch CC; Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. conor.lynch@moffitt.org., Basanta D; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. david@cancerevo.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 19; Vol. 15 (1), pp. 2458. Date of Electronic Publication: 2024 Mar 19.
DOI: 10.1038/s41467-024-46594-0
Abstrakt: Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.
(© 2024. The Author(s).)
Databáze: MEDLINE
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