Abstract
RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been sufficiently characterized. In this study we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 (KRC) in exocrine cells. We demonstrate that Rnf43 loss results in an increased incidence of high-grade cystic lesions of the pancreas and PDAC. Importantly, KRC mice have a significantly decreased survival compared to mice containing only an oncogenic Kras mutation. By use of single cell RNA sequencing we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the Kras/Tp53 driven PDAC GEMM. Furthermore, expression of the chemokine, CXCL5, was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. This GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Disclosures A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to ThriveEarlier Detection. All other authors are free of conflicts of interest and have nothing to disclose.
Funding Sources AM is supported by NIH grants R01 CA220236 and R01 CA218004. AM is also funded by the Sheikh Khalifa Bin Zayed Foundation