Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

• DOI: 10.1016/j.hbpd.2022.12.003
• Publication Date: 2022-12-14T01:09:41Z
• Authors: Denis Revskij; Jakob Runst; Camilla Umstätter; Luise Ehlers; Sarah Rohde; Dietmar Zechner; Manuela Bastian; Brigitte Müller-H...; Georg Fuellen; Larissa Henze; Hugo Murua Escobar; Christian Junghanss; Axel Kowald; Uwe Walter; Rüdiger Köhling; Olaf Wolkenhauer; Robert Jaster
• Keywords: Knockout mouse; Tumor progression; Pancreatic tumor

Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown.We took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment.Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells.Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.