Universität zu Köln

Vorhagen, Susanne, Kleefisch, Dominik, Persa, Oana-Diana, Graband, Annika, Schwickert, Alexandra, Saynisch, Michael, Leitges, Michael, Niessen, Carien M. and Iden, Sandra ORCID: 0000-0003-2333-9827 (2018). Shared and independent functions of aPKC lambda and Par3 in skin tumorigenesis. Oncogene, 37 (37). S. 5136 - 5147. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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 aPKC. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vorhagen, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleefisch, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Persa, Oana-Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Graband, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwickert, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Saynisch, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Leitges, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Niessen, Carien M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Iden, Sandra UNSPECIFIED orcid.org/0000-0003-2333-9827 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-172981
DOI:	10.1038/s41388-018-0313-1
Journal or Publication Title:	Oncogene
Volume:	37
Number:	37
Page Range:	S. 5136 - 5147
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POLARITY PROTEIN PAR3; NF-KAPPA-B; CELL POLARITY; EPIDERMAL HOMEOSTASIS; BREAST-CANCER; CARCINOGENESIS; STAT3; DIFFERENTIATION; COMPLEX; TUMORS Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17298