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  3. Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy

Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy

  • Cell. 2024 Sep 4:S0092-8674(24)00904-8. doi: 10.1016/j.cell.2024.08.013.
Yash Chhabra 1,  Mitchell E Fane 2,  Sneha Pramod 3,  Laura Hüser 3,  Daniel J Zabransky 4,  Vania Wang 3,  Agrani Dixit 3,  Ruzhang Zhao 5,  Edwin Kumah 3,  Megan L Brezka 3,  Kevin Truskowski 2,  Asmita Nandi 3,  Gloria E Marino-Bravante 3,  Alexis E Carey 3,  Naina Gour 6,  Devon A Maranto 7,  Murilo R Rocha 3,  Elizabeth I Harper 3,  Justin Ruiz 3,  Evan J Lipson 7,  Elizabeth M Jaffee 8,  Kristin Bibee 9,  Joel C Sunshine 9,  Hongkai Ji 5,  Ashani T Weeraratna 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: yash.chhabra@fccc.edu.
  • 2 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 3 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
  • 4 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 5 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
  • 6 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 7 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 8 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA; The Cancer Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 9 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 10 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: aweerar1@jhu.edu.
PMID: 39243764 DOI: 10.1016/j.cell.2024.08.013
Abstract

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing Axl expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRaf/MEK inhibition.

Keywords

DNA damage; aging; epigenetics; fibroblast; melanoma; metastasis; senescence; sex dimorphism; sex disparity; therapy resistance; tumor microenvironment.

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