Molecular and genetic interaction of the polarity proteins Par3 and aPKC in skin carcinogenesis

非黑色素瘤皮肤癌是世界上最常见的癌症之一，由于预期寿命延长和日晒增加，发病率仍在增加。有趣的是，肿瘤环境在皮肤癌的进展中起着决定性作用。肿瘤细胞极性和结构的改变是癌症的标志，与癌症的生长、侵袭和转移有关。决定肿瘤细胞结构及其周围环境如何交流以促进或抑制癌症的机制在很大程度上是未知的。在此之前，我们已经发现极性蛋白aPKCl和Par3在表皮干细胞维持、角质细胞分化和存活以及皮肤炎症的调节中起着至关重要的作用，它们可以形成复合物。最重要的是，表皮Par3的失活抑制了乳头状瘤的形成，但促进了角棘瘤的形成。这些肿瘤被认为起源于不同的细胞群，这表明Par3在不同的皮肤肿瘤中具有环境依赖性作用。在本提案中，我们将结合我们的专业知识和我们实验室生成的不同小鼠模型，探讨aPKCl和Par3在皮肤肿瘤促进和抑制中是否具有重叠或不同的作用。我们将探讨Par3和aPKCl的改变控制肿瘤发生和进展的潜在机制，以及肿瘤细胞结构的这些改变如何影响与微环境的交流，从而驱动或抑制肿瘤的发生。

Non-melanoma skin cancer is among the most common cancers worldwide with a still increasing incidence due to longer life expectancy and rising sun exposure. Interestingly, the tumor environment plays a decisive role in skin cancer progression. Alterations in polarity and architecture of tumor cells are hallmarks of cancers and have been implicated in cancer growth, invasion and metastasis. The mechanisms that determine how the tumor cyto-architecture and its surroundings communicate to either promote or inhibit cancer are largely unknown. Previously we have identified a crucial role for the polarity proteins aPKCl and Par3, which can form a complex, in the regulation of epidermal stem cell maintenance, keratinocyte differentiation and survival as well as skin inflammation. Most importantly, epidermal inactivation of Par3 inhibits papilloma formation but promotes keratoacanthoma formation. These tumors are thought to arise from different cell populations, indicating a context-dependent role for Par3 in different skin tumors. In the present proposal we will ask whether aPKCl and Par3 have overlapping or different roles in skin tumor promotion and suppression by combining our expertise and different mouse models generated in our laboratories. We will address the underlying mechanisms by which alterations in Par3 and aPKCl control tumor initiation and progression and address how these alterations in tumor cell architecture affect the communication with the microenvironment to either drive or inhibit tumorigenesis.