Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

Abstract

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 aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ 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 aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

“…It will be interesting to identify how niche-specific mechanical regulation contributes to mitotic fidelity and resulting genome integrity of different epithelia. Finally, given the plethora of effects that DNA damage can yield in both tissue and cancer stem cells 72 , and the consistent stabilization of p53 we observed upon Par3 loss (this study), it will be interesting to dissect in the future if mechanisms similar to those identified here underlie Par3-dependent and/or aPKCλ-dependent skin tumorigenesis 30,73 .…”

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

“…Although our findings clearly implicate defective mitosis in the increased epidermal differentiation, they do not exclude that additional mechanisms such as local force coupling between non-mitotic and mitotic neighbors 45 further contribute to premature differentiation upon Par3 loss. Finally, given the plethora of effects that DNA damage can yield in both tissue and cancer stem cells 47 , it will be interesting to dissect in the future if mechanisms similar to those identified here underlie Par3-and/or aPKCdependent skin tumorigenesis 28,48 . Figure 6.…”

Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer

“…Evidence indicates a similar dual role in skin cancer. Whereas aPKCl and PAR3 promote papilloma formation (Iden et al, 2012;Vorhagen et al, 2018) and BCC (Atwood et al, 2013), PAR3 inhibits keratoacanthoma and human SCC (Iden et al, 2012;Ling et al, 2020).…”

“…Given that the local regulation of mechanics and BM turnover determines the extent of tissue deformation, one might thus hypothesize that the local biomechanical state of the tumor-initiating cells and the surrounding niche determine whether disturbed polarity promotes or inhibits carcinogenesis. For example, PAR3/aPKC-dependent regulation of proliferation and survival of mutant papilloma cells depend on intercellular contacts (Iden et al, 2012;Vorhagen et al, 2018). In a human SCC model, oncogenic HRAS promoted the loss of PAR3 to disturb E-cadherin and epithelial architecture, which, interestingly, preceded hyperplasia (Ling et al, 2020).…”