Cell Death Differ.: co-auth.: W.Wahli

 2020 Apr 20. doi: 10.1038/s41418-020-0535-y. [Epub ahead of print]

Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.

Tan MWY1,2Sng MK3Cheng HS1,3Low ZS3Leong BJJ1Chua D1Tan EHP1Chan JSK1Yip YS1,3Lee YH3Pal M4Wang X3,5,6,7Wahli W3,8,9Tan NS10,11.


The incidence of nonmelanoma skin cancer (NMSC) has been increasing worldwide. Most studies have highlighted the importance of cancer-associated fibroblasts (CAFs) in NMSC progression. However much less is known about the communication between normal fibroblasts and epithelia; disruption of this communication affects tumor initiation and the latency period in the emergence of tumors. Delineating the mechanism that mediates this epithelial-mesenchymal communication in NMSC could identify more effective targeted therapies. The nuclear receptor PPARβ/δ in fibroblasts has been shown to modulate adjacent epithelial cell behavior, however, its role in skin tumorigenesis remains unknown. Using chemically induced skin carcinogenesis, we showed that FSPCre-Pparb/dex4 mice, whose Pparb/d gene was selectively deleted in fibroblasts, had delayed emergence and reduced tumor burden compared with control mice (Pparb/dfl/fl). However, FSPCre-Pparb/dex4-derived tumors showed increased proliferation, with no difference in differentiation, suggesting delayed tumor initiation. Network analysis revealed a link between dermal Pparb/d and TGF-β1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARβ/δ deficiency in fibroblasts increased epidermal Nox4-derived H2O2 production, which triggered an NRF2-mediated antioxidant response. We further showed that H2O2 upregulated NRF2 mRNA via the B-Raf-MEK1/2 pathway. The enhanced NRF2 response altered the activities of PTEN, Src, and AKT. In vivo, we detected the differential phosphorylation profiles of B-Raf, MEK1/2, PTEN, Src, and AKT in the vehicle-treated and chemically treated epidermis of FSPCre-Pparb/dex4 mice compared with that in Pparb/dfl/fl mice, prior to the first appearance of tumors in Pparb/dfl/fl. Our study revealed a role for fibroblast PPARβ/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis.

PMID: 32313198