ArticleCell2024
Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy.
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Article in Cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 2 of them syntheses that pooled it.
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42citing papers in PubMed, 2 pooled it
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Who cites it
42 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- MicroRNAs and Cellular Senescence in Melanoma: An Underexplored Link to Tumor Progression-A Systematic Review with Bioinformatics Analyses.International journal of molecular sciences · 2026Pooled it
- What is the optimal first-line regimen for advanced non-small cell lung cancer patients with epidermal growth factor receptor mutation: a systematic review and network meta-analysis.BMC pulmonary medicine · 2024Pooled it
- AXL at the nexus of therapeutic resistance, tumor vascularization, and immune evasion in cancer.iScience · 2026Review
- Lymph node contraction links sex-biased naive CD8Nature aging · 2026Article
- Supermeres Containing the Discoidin Domain Receptor 1 Extracellular Domain Promote Collagen Alignment and Immune Exclusion in Microsatellite-Stable Colorectal Cancer.Cancer research communications · 2026Article
- Supramolecular Assembly of Stepped-Persistent ROS Nanogenerator for Sustained Tumor Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Epigenetic dynamics of cellular senescence: From mechanistic insights to precision senotherapy.Chinese medical journal · 2026Review
- A pan-cancer single-cell atlas uncovers the role of sex hormones and chromosomes in sex-divergent reprogramming of the tumor microenvironment.Cell communication and signaling : CCS · 2026Article
- Protocol for generation, time-course imaging, and automated quality control of 3D spheroid invasion using TRACEQC.STAR protocols · 2026Article
- An Itch Receptor Drives Melanoma.bioRxiv : the preprint server for biology · 2026Article
- Metabolic Crosstalk Between Host and Tumor as a Circuit of Resilience in Cancer Therapy.Cells · 2026Review
- High-yield isolation and characterization of microvascular niche cells from human full-thickness skin biopsies.Scientific reports · 2026Article
- HCCaging: a liver physiological aging-related biomarker for hepatocellular carcinoma diagnosis based on transcriptome data.npj aging · 2026Article
- A photothermal immune hydrogel dressing for enhanced post-melanoma resection treatment.Journal of nanobiotechnology · 2026Article
- Androgen receptor-dependent DRAM1 activation drives autophagic resistance to BRAF inhibitors in BRAFV600-mutant melanoma.Cell death & disease · 2026Article
- BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations.Molecular biomedicine · 2026Review
- Sexual dimorphism in cancer: molecular mechanisms and precision oncology perspectives.Biology of sex differences · 2026Review
- Immune landscape of melanoma: Tumor microenvironment, resistance mechanisms, and predictive biomarkers.World journal of clinical oncology · 2026Review
- The gut-skin axis in melanoma: from microbial regulatory mechanisms to clinical translation for precision management.Frontiers in microbiology · 2026Review
Corrections and comments
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Authors and funding
25 authors.
Yash ChhabraDepartment 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.
Mitchell E FaneDepartment 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.
Sneha PramodDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Laura HüserDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Daniel J ZabranskyDepartment 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.
Vania WangDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Agrani DixitDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Ruzhang ZhaoDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Edwin KumahDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Megan L BrezkaDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Kevin TruskowskiDepartment 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.
Asmita NandiDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Gloria E Marino-BravanteDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Alexis E CareyDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Naina GourDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Devon A MarantoDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA.
Murilo R RochaDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Elizabeth I HarperDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Justin RuizDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Evan J LipsonDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA.
Elizabeth M JaffeeDepartment 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.
Kristin BibeeDepartment of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Joel C SunshineDepartment of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Hongkai JiDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Ashani T WeeraratnaDepartment 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.
Funding
Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9MTargeting the MAP and PI3 Kinase Pathways in MelanomaP01CA114046 · NCI · WISTAR INSTITUTE · PI HERLYN, MEENHARD F, WEERARATNA, ASHANI T · 2008 to 2023
$37.1MONCOLOGY: CHEMOTHERAPY, IMMUNOLOGY, BIOLOGYT32CA009071 · NCI · JOHNS HOPKINS UNIVERSITY · PI Mary Y Armanios, Nilofer S. Azad · 1985 to 2026
$12.8MT32: Predoctoral and Postdoctoral Training Program in Nanotechnology for Cancer ResearchT32CA153952 · NCI · JOHNS HOPKINS UNIVERSITY · PI Denis Wirtz · 2015 to 2026
$3.5MA plasticity and reprogramming paradigm for therapy resistance at the single cell levelU01CA227550 · NCI · UNIVERSITY OF PENNSYLVANIA · PI RADHAKRISHNAN, RAVI, RAJ, ARJUN · 2018 to 2022
$3.3MAn integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skinR01CA232256 · NCI · WISTAR INSTITUTE · PI CUKIERMAN, EDNA, RAJ, ARJUN · 2019 to 2023
$3.0MEffect of the aged microenvironment on tumor dormancyR01CA207935 · NCI · WISTAR INSTITUTE · PI WEERARATNA, ASHANI T · 2017 to 2021
$2.0MComputational tools for regulome mapping using single-cell genomic dataR01HG010889 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI JI, HONGKAI · 2019 to 2022
$1.6MThe role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancyR00CA263017 · NCI · RESEARCH INST OF FOX CHASE CAN CTR · PI FANE, MITCHELL EDWARD · 2023 to 2025
$747kIntegrative Analysis of the Aging Peritoneum in Metastatic ReceptivityK00AG068527 · NIA · JOHNS HOPKINS UNIVERSITY · PI HARPER, ELIZABETH · 2023 to 2025
$223kThe role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancyK99CA263017 · NCI · JOHNS HOPKINS UNIVERSITY · PI FANE, MITCHELL EDWARD · 2022 to 2022
$121kEffect of Age-Dependent Loss of HAPLN1 on Vascular Integrity and Melanoma MetastasisF31CA261065 · NCI · JOHNS HOPKINS UNIVERSITY · PI MARINO, GLORIA ELIZABETH · 2022 to 2022
$43kNCI NIH HHS F31 CA261065NCI NIH HHS K99 CA263017NCI NIH HHS P01 CA114046NCI NIH HHS P30 CA010815NCI NIH HHS R00 CA263017NCI NIH HHS R01 CA207935NCI NIH HHS R01 CA232256NCI NIH HHS T32 CA009071NCI NIH HHS T32 CA153952NCI NIH HHS U01 CA227550NHGRI NIH HHS R01 HG010889NIA NIH HHS K00 AG068527
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.
Indexed as
Bone Morphogenetic Protein 2Drug Resistance, NeoplasmEnhancer of Zeste Homolog 2 ProteinMelanomaTumor MicroenvironmentAgingAnimalsAxl Receptor Tyrosine KinaseCell Line, TumorCell ProliferationCellular SenescenceFemaleFibroblastsHumansMaleMiceAxl Receptor Tyrosine KinaseBMP2 protein, humanBone Morphogenetic Protein 2Enhancer of Zeste Homolog 2 ProteinEZH2 protein, humanEzh2 protein, mouseProto-Oncogene ProteinsProto-Oncogene Proteins B-rafReceptor Protein-Tyrosine KinasesagingDNA damageepigeneticsfibroblastmelanomametastasissenescencesex dimorphismsex disparitytherapy resistancetumor microenvironment
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