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

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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.