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<p>One of the main characteristics of solid tumors, such as melanoma, is an acidic tumor microenvironment. Due to dysregulation of the cancer cell metabolism and an increased production of acidic metabolites, the tumor acidifies its microenvironment. We hypothesize that this has a strong impact on tumor heterogeneity and the formation of phenotypic subpopulations. Cell culture experiments are usually carried out at a physiological pH of 7.4. Here, we show that long-time acidosis results in the formation of a senescent subpopulation in melanoma cells. Interestingly, after reintroduction to physiological pH, these cells lose their senescence-associated attributes. We isolated this subpopulation using β-galactosidase-dependent C<sub>12</sub>FDG staining and FACS. Live cell imaging, microscopy, and RNA sequencing analysis revealed that these apparent senescent cells show an increased migratory activity. With this study, we demonstrate that the acidic tumor microenvironment drives tumor plasticity in melanoma and results in the formation of a small subpopulation, which promotes metastasis.</p><p></p>

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Acidic melanoma microenvironment selects for a senescence-like but also migratory-active subpopulation driving metastatic disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月20日

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  • Chafia Chiheb,
  • Stefan Fischer,
  • Zubeir El Ahmad,
  • Ingmar Henz,
  • Ines Böhme-Schäfer,
  • Melanie Kappelmann-Fenzl,
  • Anja Katrin Bosserhoff

摘要

One of the main characteristics of solid tumors, such as melanoma, is an acidic tumor microenvironment. Due to dysregulation of the cancer cell metabolism and an increased production of acidic metabolites, the tumor acidifies its microenvironment. We hypothesize that this has a strong impact on tumor heterogeneity and the formation of phenotypic subpopulations. Cell culture experiments are usually carried out at a physiological pH of 7.4. Here, we show that long-time acidosis results in the formation of a senescent subpopulation in melanoma cells. Interestingly, after reintroduction to physiological pH, these cells lose their senescence-associated attributes. We isolated this subpopulation using β-galactosidase-dependent C12FDG staining and FACS. Live cell imaging, microscopy, and RNA sequencing analysis revealed that these apparent senescent cells show an increased migratory activity. With this study, we demonstrate that the acidic tumor microenvironment drives tumor plasticity in melanoma and results in the formation of a small subpopulation, which promotes metastasis.