Effects of an acidic tumor microenvironment on human melanoma

在治疗中幸存下来的小亚群肿瘤细胞可以留在体内，使肿瘤复发。目前，这些亚群的特征在癌症研究领域具有重要意义。在黑色素瘤中，慢周期癌细胞表现出分子重编程，包括低小眼球相关转录因子(MITF)因子和染色质重塑因子Jumonji/ARID结构域包含蛋白1B(JARID1B)。在这里，MITFlow/AXL高表型具有相关性，因为它与肿瘤化疗耐药和侵袭性相关。我们先前的研究表明，微环境酸中毒(pH 6.7)诱导人黑色素瘤出现衰老样表型，表现为MITFlow/AXL高签名、翻译重编程和化疗耐药性增加。我们认为，肿瘤内酸中毒促使肿瘤组织中的表型可塑性朝着不同的肿瘤亚群--特别是衰老的亚群--的发展，这反过来又影响周围的肿瘤细胞，并随后导致耐药表型。我们项目提案的目的是鉴定和表征酸中毒诱导的亚群(S)，并阐明衰老样群是否影响周围的肿瘤细胞。此外，我们将确定哪些分子负责或功能上参与表型的诱导。对这些关键角色的分子作用的了解也将有助于开发未来针对药物残留亚群的治疗方法。

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.