Methionine-producing tumor micro(be) environment fuels growth of solid tumors.

Autor: Vega AA; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.; Brown Cancer Center, University of Louisville School of Medicine, 505 S. Hancock St. Rm 204, Louisville, KY, 40202, USA., Marshall EA; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada., Noonan AJC; Genome Science and Technology Program, University of British Columbia, Vancouver, BC, Canada.; ECOSCOPE Training Program, University of British Columbia, Vancouver, BC, Canada., Filho FSL; Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada., Yang J; Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada., Stewart GL; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada., Johnson FD; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada., Vucic EA; NYU Langone Medical Center, New York, NY, USA., Pewarchuk ME; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada., Shah PP; Brown Cancer Center, University of Louisville School of Medicine, 505 S. Hancock St. Rm 204, Louisville, KY, 40202, USA., Clem BF; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA.; Brown Cancer Center, University of Louisville School of Medicine, 505 S. Hancock St. Rm 204, Louisville, KY, 40202, USA., Nislow C; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Lam S; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada., Lockwood WW; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Hallam SJ; Genome Science and Technology Program, University of British Columbia, Vancouver, BC, Canada.; ECOSCOPE Training Program, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology & Immunology, University of British Columbia, Vancouver, BC, Canada.; Bioinformatics Program, University of British Columbia, Vancouver, BC, Canada.; Biofactorial High-Throughput Biology Facility, University of British Columbia, Vancouver, BC, Canada., Leung JM; Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada., Beverly LJ; Brown Cancer Center, University of Louisville School of Medicine, 505 S. Hancock St. Rm 204, Louisville, KY, 40202, USA. Levi.Beverly@Louisville.edu., Lam WL; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2023 Dec; Vol. 46 (6), pp. 1659-1673. Date of Electronic Publication: 2023 Jun 15.
DOI: 10.1007/s13402-023-00832-7
Abstrakt: Background: Recent studies have uncovered the near-ubiquitous presence of microbes in solid tumors of diverse origins. Previous literature has shown the impact of specific bacterial species on the progression of cancer. We propose that local microbial dysbiosis enables certain cancer phenotypes through provisioning of essential metabolites directly to tumor cells.
Methods: 16S rDNA sequencing of 75 patient lung samples revealed the lung tumor microbiome specifically enriched for bacteria capable of producing methionine. Wild-type (WT) and methionine auxotrophic (metA mutant) E. coli cells were used to condition cell culture media and the proliferation of lung adenocarcinoma (LUAD) cells were measured using SYTO60 staining. Further, colony forming assay, Annexin V Staining, BrdU, AlamarBlue, western blot, qPCR, LINE microarray and subcutaneous injection with methionine modulated feed were used to analyze cellular proliferation, cell-cycle, cell death, methylation potential, and xenograft formation under methionine restriction. Moreover, C 14 -labeled glucose was used to illustrate the interplay between tumor cells and bacteria.
Results/discussion: Our results show bacteria found locally within the tumor microenvironment are enriched for methionine synthetic pathways, while having reduced S-adenosylmethionine metabolizing pathways. As methionine is one of nine essential amino acids that mammals are unable to synthesize de novo, we investigated a potentially novel function for the microbiome, supplying essential nutrients, such as methionine, to cancer cells. We demonstrate that LUAD cells can utilize methionine generated by bacteria to rescue phenotypes that would otherwise be inhibited due to nutrient restriction. In addition to this, with WT and metA mutant E. coli, we saw a selective advantage for bacteria with an intact methionine synthetic pathway to survive under the conditions induced by LUAD cells. These results would suggest that there is a potential bi-directional cross-talk between the local microbiome and adjacent tumor cells. In this study, we focused on methionine as one of the critical molecules, but we also hypothesize that additional bacterial metabolites may also be utilized by LUAD. Indeed, our radiolabeling data suggest that other biomolecules are shared between cancer cells and bacteria. Thus, modulating the local microbiome may have an indirect effect on tumor development, progression, and metastasis.
(© 2023. The Author(s).)
Databáze: MEDLINE
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