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

肿瘤是一种病理结构，包括处于几种分化状态的异质细胞亚群。最去分化和多能自我更新分化的亚群是肿瘤干细胞(CSCs)。最新的发现表明，CSCs是一个多功能的亚群，未分化的干细胞样瘤细胞和分化的亚群之间的相互转化发生在肿瘤内，建立了一种动态平衡。这种细胞特性的可塑性是由上皮-间充质转化(EMT)级联介导的，该级联在非CSC和CSC状态之间切换，以促进癌症的侵袭。靶向控制肿瘤干细胞/分化平衡和促进细胞异质性的机制是防止向转移阶段进展的一种有吸引力的策略。P73基因是一种p53同源基因，它同时产生抑癌基因(TAp73)和致癌基因(DNp73)亚型。我们提供了DNp73以转录因子为基础的作用模式诱导EMT介导的干性和侵袭性的第一个证据。这是否通过同时调节分化来协调，DNp73如何改变肿瘤微环境以利于转移，以及TAp73是否拮抗这一作用，尚不清楚。我们的初步数据预测，DNp73驱动的干细胞伴随着神经分化的调节，支持最近发现的但仍然神秘的神经癌细胞串扰导致新的神经发生。这种DNp73效应似乎严重依赖于一种基于蛋白质-蛋白质相互作用的机制，在这种机制中，p73亚型可能与分化/神经发育因子相互作用，以p73反应元件依赖和独立的方式共同调节基因。在这个项目中，我们旨在研究DNp73对肿瘤内CSC/非CSC平衡以及与TAp73相关的周围微环境的影响，并确定与侵袭性表型相关的辅助调节-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，我们将针对新发现的目标化合物重新定位或开发药物抑制剂。揭示p73介导的干细胞分化的机制对恶性转化过程有重要的洞察力，并为抗转移治疗带来巨大的希望。

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.