Effects of an acidic tumor microenvironment on human melanoma

在治疗中存活下来的肿瘤细胞的一小部分亚群可以留在体内并使肿瘤复发。这些亚群的表征目前在癌症研究领域非常重要。在黑色素瘤中，慢循环癌细胞显示分子重编程，包括低微眼相关转录因子（MITF）因子和染色质重塑因子Jumonji/ARID结构域含蛋白1B （JARID1B）。在这里，MITFlow/AXLhigh表型是相关的，因为它与肿瘤化疗耐药性和侵袭性有关。我们之前的研究表明，微环境酸中毒（pH 6.7）在人类黑色素瘤中诱导衰老样表型，具有MITFlow/AXLhigh特征，翻译重编程和化疗耐药性增加。我们假设，肿瘤内酸中毒驱动肿瘤组织的表型可塑性，从而导致不同肿瘤亚群的发展，尤其是衰老样亚群，这反过来影响周围的肿瘤细胞，并随后导致治疗抗性表型。我们项目提案的目的是识别和表征酸中毒诱导的亚群，并阐明衰老样种群是否影响周围的肿瘤细胞。此外，我们将确定负责或在功能上参与诱导表型的分子。了解这些关键角色的分子作用也将有助于开发针对药物存活亚群的未来治疗方法。

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.