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MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%–30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and...

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Autores principales: Nirala, Bikesh K., Patel, Tajhal D., Kurenbekova, Lyazat, Shuck, Ryan, Dasgupta, Atreyi, Rainusso, Nino, Coarfa, Cristian, Yustein, Jason T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371352/
https://www.ncbi.nlm.nih.gov/pubmed/37279073
http://dx.doi.org/10.1172/jci.insight.164947
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author Nirala, Bikesh K.
Patel, Tajhal D.
Kurenbekova, Lyazat
Shuck, Ryan
Dasgupta, Atreyi
Rainusso, Nino
Coarfa, Cristian
Yustein, Jason T.
author_facet Nirala, Bikesh K.
Patel, Tajhal D.
Kurenbekova, Lyazat
Shuck, Ryan
Dasgupta, Atreyi
Rainusso, Nino
Coarfa, Cristian
Yustein, Jason T.
author_sort Nirala, Bikesh K.
collection PubMed
description Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%–30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-Myc(T58A) p53(fl/+) knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag–MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape.
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spelling pubmed-103713522023-07-27 MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma Nirala, Bikesh K. Patel, Tajhal D. Kurenbekova, Lyazat Shuck, Ryan Dasgupta, Atreyi Rainusso, Nino Coarfa, Cristian Yustein, Jason T. JCI Insight Research Article Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%–30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-Myc(T58A) p53(fl/+) knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag–MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape. American Society for Clinical Investigation 2023-07-10 /pmc/articles/PMC10371352/ /pubmed/37279073 http://dx.doi.org/10.1172/jci.insight.164947 Text en © 2023 Nirala et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Nirala, Bikesh K.
Patel, Tajhal D.
Kurenbekova, Lyazat
Shuck, Ryan
Dasgupta, Atreyi
Rainusso, Nino
Coarfa, Cristian
Yustein, Jason T.
MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title_full MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title_fullStr MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title_full_unstemmed MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title_short MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma
title_sort myc regulates csf1 expression via microrna 17/20a to modulate tumor-associated macrophages in osteosarcoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371352/
https://www.ncbi.nlm.nih.gov/pubmed/37279073
http://dx.doi.org/10.1172/jci.insight.164947
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