PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma

Kumar, Prakrit R., Saad, Mona, Hellmich, Charlotte, Mistry, Jayna J., Moore, Jamie A., Conway, Shannon, Morris, Christopher J. ORCID: https://orcid.org/0000-0002-7703-4474, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526, Moncrieff, Marc D. and Rushworth, Stuart A. (2022) PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma. British Journal of Cancer, 127. 69–78. ISSN 0007-0920

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Abstract

Introduction: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. Methods: Primary melanoma cells, and MSCs derived from patients were obtained. Genes’ expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. Results: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. Conclusion: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.

Item Type: Article
Additional Information: Acknowledgements: The authors wish to thank the Norwich Research Park (NRP), The Rosetrees Trust, The Big C and The NHS. SAR is supported by the MRC project grant (MR/T02934X/1). CH is funded by the Wellcome Trust clinical fellowship program. The authors also thank Dr. Allyson Tyler and Dr. Karen Ashurst from the Laboratory Medicine Department at the Norfolk and Norwich University Hospital for technical assistance. The authors also wish to thank the team at the Disease Modelling Unit of the University of East Anglia for assistance with the in-vivo studies. pCDH-LucferaseT2A-mCherry was kindly gifted by Professor Irmela Jeremias, MD, from Helmholtz Zentrum München, Munich, Germany. We also acknowledge Earlham Institute using support from the UK Research and Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC) under grants National Capability in Genomics and Single Cell “BBS/E/T/000PR9816.
Uncontrolled Keywords: oncology,cancer research ,/dk/atira/pure/subjectarea/asjc/2700/2730
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 31 Mar 2022 12:30
Last Modified: 22 Oct 2022 17:40
URI: https://ueaeprints.uea.ac.uk/id/eprint/84399
DOI: 10.1038/s41416-022-01783-w

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