Vavinskaya, V. | bioRxiv Science

bioRxiv2020

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens. We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its non-canonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1). Correspondingly, inhibition of RNF125 expression enhanced organoid growth in culture and orthotopic tumor development. Conversely, restoration of PDX1 levels in human or mouse PDA cells and organoids depleted of RNF125, inhibited cell proliferation and growth, while expression of HDAC2 enhanced it. Notably, higher expression of RNF125 and PDX1 coincided with differentiated tumor phenotypes, and better outcome in PDA patients. In demonstrating the importance of RNF125 control of PDX1 expression via HDAC2 ubiquitination in PDA development, our findings highlight markers (RNF125, PDX1) and targets (HDAC2) for monitoring and possible treatment of PDA.

cancer biology↗

bioRxiv2019

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar to ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis. SignificanceWe find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type.

cancer biology↗