ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

Abstract

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of b-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

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“…TRIM29 seems to be a key regulator of epithelial-mesenchymal transition (EMT) and tumor invasion, but its roles among neoplasms are controversial. It upregulates CD44 and induces EMT in K-ras-induced pancreatic carcinoma (48). On the contrary, it also suppresses TWIST1 and inhibits EMT in breast carcinoma (49).…”

Early evidence for the role of TRIM29 in multiple cancer models

“…[13] These reports showed one of the functional roles of TRIM29 in human pancreatic adenocarcinomas and indicated the possibility of TRIM29 being a potential therapeutic target in pancreatic cancer. However, in lung cancer cells, TRIM29 upregulates c-Myc and cyclin D via activation of the NF-κB pathway but independently of the canonical Wnt signaling pathway.…”

“…IKKα seems to negatively regulate TRIM29 expression in an epigenetic manner [16] (Figure 1). Oncogenic KRAS upregulates TRIM29 expression, leading to the induction of an EMT via the canonical Wnt signaling pathway in pancreatic cancers [13] (Figure 1). The TRIM29 gene was identified as a potential target of miR-185 in gastric cancer.…”

Pancreatic cancer: from bench to bedside

“…Bhattacharjee (7) pointed out that cancer can hijack the vitamin D receptor, repair cells damaged by chemotherapy; it is a key way to escape chemotherapy for pancreatic cancer. The researchers also found that the gene-ATDC (ataxia telangiectasia group D complementing gene) takes part in 90% of the growth and proliferation of pancreatic cancer; it plays a key role from the early development of invasive cancer to the metastatic cancer; it reveals the reason why patients with early pancreatic cancer has only a 30% survival rate, that even in the very early stages of invasive cancer, cancer cells have been transferred (8). Gene mutation is the key to the occurrence of cancer, and more than 95% of pancreatic cancer patients have KRAS mutations.…”