Effects of an acidic tumor microenvironment on human melanoma

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Small subpopulations of tumor cells that survive therapies can remain in the body and enable tumor relapse. Characterization of these subpopulations is currently of great importance in the field of cancer research. In melanoma, slow-cycling cancer cells show molecular reprogramming including low microphthalmia-associated transcription factor (MITF) factor and chromatin remodeling factor Jumonji/ARID Domain-Containing Protein 1B (JARID1B). Here, the MITFlow/AXLhigh phenotype is of relevance because it is associated with tumor chemotherapy resistance and invasiveness. Our previous research shows that microenvironmental acidosis (pH 6.7) induces a senescent-like phenotype in human melanoma with a MITFlow/AXLhigh signature, translation reprogramming and increased chemotherapeutic resistance. We assume that intratumoral acidosis drives phenotypic plasticity in the tumor tissue toward development of different tumor subpopulations – especially a senescent-like subpopulation, which in turn influences surrounding tumor cells and subsequently contributes to a therapy resistant phenotype. The aim of our project proposal is to identify and characterize the acidosis-induced subpopulation(s) and to clarify whether the senescence-like population influence surrounding tumor cells. Further, we will identify molecules which are responsible for or functionally involved in the induction of the phenotypes. The understanding of the molecular role of such key players will also help developing future therapeutic treatment against drug surviving subpopulations.