Function of p73 in stemness/differentiation equilibrium and intratumoral cellular heterogeneity: mechanistic insights and anti-metastatic targeting

p73 在干性/分化平衡和瘤内细胞异质性中的功能：机制见解和抗转移靶向

• 批准号: 349395700
• 负责人: Professorin Dr. Brigitte M. Pützer
• 金额: --
• 依托单位: Institut für Experimentelle Gentherapie und Tumorforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/349395700?language=en
• 关键词: Function; p73; stemness; differentiation; equilibrium

Tumors are pathological structures encompassing heterogeneous cell subpopulations in several differentiation states. The most de-differentiated and pluripotent subpopulations capable of self-renewal and differentiation are cancer stem cells (CSCs). Latest findings suggest that CSCs are a versatile subpopulation and that interconversion between undifferentiated stem-like tumor cells and differentiated subpopulations occurs within the tumor establishing a dynamic balance. This plasticity in cellular identity is mediated by epithelial-mesenchymal transition (EMT) cascades, which switch between non-CSC and CSC states to facilitate cancer invasiveness. Targeting the mechanisms that control the stemness/differentiation equilibrium and fuel cellular heterogeneity of tumors is an appealing strategy to prevent progression towards metastatic stages. The p73 gene, a p53 homologue, generates both anti-oncogenic (TAp73) and oncogenic (DNp73) isoforms. We provided first evidence that DNp73 induces EMT-mediated stemness and aggressiveness in a transcription factor-based mode of action. Whether this is orchestrated by simultaneous modulation of differentiation, how DNp73 alters the tumor microenvironment in favor of metastasis, and if TAp73 antagonizes this effect, is unknown. Our preliminary data predict that DNp73-driven stemness is accompanied by regulation of neurodifferentiation, supporting a recently-recognized, but still enigmatic nerve-cancer cell cross-talk causing neoneurogenesis. This DNp73 effect seems to critically depend on an understudied protein-protein interaction-based mechanism, where p73 isoforms may interact with differentiation/neurodevelopmental factors to coregulate genes in a p73 responsive element-dependent and independent manner. In this project, we aim to investigate the effect of DNp73 on the intratumoral CSC/non-CSC equilibrium and in the surrounding microenvironment relative to TAp73 and to identify the coregulator-target gene axes associated with the aggressive phenotype. These potentially metastasis-relevant factors will be functionally characterized in established mouse metastasis models and validated on patient samples. Aided by structural systems pharmacology, we will repurpose or develop pharmacological inhibitors against newly uncovered target complexes. Unveilling the mechanisms of p73-mediated stemness and differentiation yields important insights into the process of malignant conversion and holds great promise for anti-metastatic therapies.

肿瘤是包含多种分化状态的异质细胞亚群的病理结构。能够自我更新和分化的去分化程度最高、多能的亚群是癌症干细胞（CSC）。最新研究结果表明，CSC 是一个多功能的亚群，未分化的干细胞样肿瘤细胞和分化的亚群之间发生相互转化，建立了动态​​平衡。细胞身份的这种可塑性是由上皮间质转化 (EMT) 级联介导的，该级联在非 CSC 和 CSC 状态之间切换以促进癌症侵袭。针对控制肿瘤干细胞/分化平衡和促进细胞异质性的机制是防止进展到转移阶段的一个有吸引力的策略。 p73 基因是 p53 同源基因，可产生抗癌 (TAp73) 和致癌 (DNp73) 亚型。我们提供了第一个证据，证明 DNp73 在基于转录因子的作用模式中诱导 EMT 介导的干性和攻击性。这是否是通过同时调节分化来协调的，DNp73如何改变肿瘤微环境以有利于转移，以及TAp73是否拮抗这种作用，尚不清楚。我们的初步数据预测，DNp73 驱动的干性伴随着神经分化的调节，支持最近认识的但仍然神秘的神经-癌细胞串扰导致新神经发生。这种 DNp73 效应似乎严重依赖于一种正在研究的基于蛋白质-蛋白质相互作用的机制，其中 p73 亚型可能与分化/神经发育因子相互作用，以 p73 响应元件依赖和独立的方式共同调节基因。在这个项目中，我们的目的是研究 DNp73 对肿瘤内 CSC/非​​ CSC 平衡以及相对于 TAp73 的周围微环境的影响，并确定与攻击性表型相关的核心调节器-靶基因轴。这些潜在的转移相关因素将在已建立的小鼠转移模型中进行功能表征，并在患者样本上进行验证。在结构系统药理学的帮助下，我们将重新利用或开发针对新发现的目标复合物的药理学抑制剂。揭示p73介导的干性和分化机制可以为恶性转化过程提供重要的见解，并为抗转移治疗带来巨大希望。