Shared and independent functions of aPKC[lambda] and Par3 in skin tumorigenesis

The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKC[lambda] serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKC[lambda] genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKC[lambda], or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKC[lambda] function as a complex to promote tumorigenesis. Molecularly, Par3/aPKC[lambda] cooperate to promote Akt, ERK and NF-[kappa]B signaling during tumor initiation to sustain growth, whereas aPKC[lambda] dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKC[lambda] cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKC[lambda] and Par3 promote a tumor-permissive environment. Importantly, aPKC[lambda] also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKC[lambda] cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.