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Phenotype screens of genetically engineered mouse models of pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like perineural invasion

ABSTRACT: Solid cancers such as pancreatic cancer (PDAC) often exploit nerves for rapid spread. This neural invasion (NI) is an independent prognostic factor in PDAC and the main trigger for local recurrence and severe pain. However, genetically engineered mouse models (GEMM) of PDAC do not adequately represent the morphology of human NI. Therefore, we performed a systematic morphological screening of mutant mice with combinations of mutant alleles of oncogenes and tumour suppressors from our mouse repository. In a newly generated TPAC and TPC mouse mutant with pancreas-specific overexpression of transforming growth factor alpha (TGFa) and conditional deletion of p53, we identified human-like NI. To dissect the molecular mechanisms behind, we compared the transcriptome of TPAC and TPC mouse mutants with known KPC and KC mice lacking NI pathology. Our results revealed strong enrichment of genes encoding the extracellular matrix, including ECM glycoproteins, collagens and proteoglycans involved in biological oxidation, nuclear receptors, and proteins encoding drug metabolism via cytochrome P450 and retinoic acid signaling in TPAC cancer cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE201994 | GEO | 2022/05/05

REPOSITORIES: GEO

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Project description:A complete understanding of molecular mechanisms that underlie cancer onset and progression could provide a basis to improve early diagnosis and more effective treatment. However, this is still a challenge in human, partly due to the difficulty of analyzing the early stages of the disease. In this context, genetically engineered mice represent a valuable alternative to model human carcinogenesis. Here, we studied cancer development in c-Myc/Tgfa transgenic mice that developed liver tumors which closely reproduce a subset of human hepatocellular carcinoma (HCC) with a poor prognosis. By using a functional genomics approach from early to late stages of HCC development, we demonstrated that hepatocarcinogenesis in c-Myc/Tgfa mice resulted from a progressive accumulation of transcriptional alterations due to an active hepatocyte proliferation in a chronic oxidative stress environment generated by a general metabolic disorder. One striking observation was the deregulation of numerous immune-related genes starting from an early stage of the disease. Particularly, we showed that activating ligands for natural killer (NK) cells were specifically induced in dysplastic hepatocytes which simultaneously lost the expression of MHC-I molecules. Besides this early mechanism of NK-mediated immune surveillance, we further reported a drastic decrease in hepatic NK cell population which may indeed contribute to the emergence and clonal expansion of progenitors for liver tumors. In conclusion, our study provided a detailed and comprehensive characterization of hepatocarcinogenesis in c-Myc/Tgfa transgenic mice and emphasized the critical role of the innate immune surveillance disruption at the early stages of liver cancer. In the present study, we reported a detailed and comprehensive dynamic characterization of the cellular and molecular alterations involved in tumor onset and progression in the liver of c-Myc/Tgfa double-transgenic mice (B6CBAxCD1 background). Liver samples from male animals were collected at various time-points ranging from 3 weeks to 9 months for c-Myc/Tgfa double-transgenic mice, or 18 months for c-Myc and Tgfa single-transgenic mice. Tissue samples were divided into two parts; one was fixed in 10% formalin for histological evaluation and the other was used for RNA analysis. Total RNAs were isolated from livers with moderate or severe hepatocyte dysplasia (at 3 weeks and 3 months, respectively), as well as from HCC and surrounding non-tumor livers (5-15 mice per group). Total RNAs were also isolated from the livers of B6CBAxCD1 wild-type mice at 3 weeks and 3 months. RNAs isolated from the normal livers of B6CBA WT mice (3 months old, n=10) were pooled and used as a common technical reference for all microarray experiments.

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Phenotype screens of genetically engineered mouse models of pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like perineural invasion

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