Wang L, Yang H, Zamperone A, Diolaiti D, Palmbos PL, Abel EV, Purohit V, Dolgalev I, Rhim AD, Ljungman M, Hadju CH, Halbrook CJ, Bar-Sagi D, di Magliano MP, Crawford HC, Simeone DM. ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. Genes Dev. 2019 Jun 1;33(11-12):641-655. doi: 10.1101/gad.323303.118. Epub 2019 May 2. PMID: 31048544; PMCID: PMC6546061.
Ataxia-Telangiectasia Group D Complementing Gene (ATDC)
Pancreatic ductal adenocarcinoma (PDA) ranks among the most lethal of human malignancies. One of the challenges in pancreatic cancer is that it is biologically aggressive and it does not respond well to chemotherapy or radiation. Our studies showed that ATDC (Trim29) significantly up-regulated in over 90% of human PDA and also highly expressed at the point when pre-cancerous cells become malignant. As a novel oncogenic protein” ATDC drives pancreatic cancer cell proliferation, invasion, and tumorigenesis via activation of the β-catenin/TCF signaling pathway by binding to Dvl2 to interrupt the function of APC/GSK3β/Axin destructing complex (Cancer Cell, 2009).
In further studies by our group to evaluate the tumorigenic function of ATDC, we generated ATDC;LSL-KrasG12D;p48-Cre (AKC) mouse in which ATDC is overexpressed in the pancreas in the setting of oncogenic KrRAS mutations. We observed that LSL-KrasG12D;p48-Cre (KC) mice developed PanINs with a long latency, and PDAC was not observed until mice reached an age of 15 months or greater. However, ATDC overexpression combined with KrasG12D accelerated PanIN progression and 85% of AKC mice at 6-8 months of age developed highly invasive and metastatic PDAC, whereas none of the age-matched KC mice displayed those lesions. It suggests, as an invasive trigger, ATDC promotes the biologic aggressiveness of pancreatic cancer. In a follow-up study, Also, by the generation of LSL-KrasG12D; p53-/+; pdx1-Cre; ATDC-/- (KPCA) mice, we demonstrated that deletion of ATDC prevents KRAS-driven acinar– ductal metaplasia (ADM), its progression to pancreatic intraepithelial neoplasia (PanIN), and PDAC development. These novel mouse models provide a platform for an improved understanding of the pathogenesis of PDAC and the development of targeted treatment strategies. Furthermore, we found that ATDC not only causes the cancer cells to grow faster and be more aggressive, but it also makes the cancer cells particularly resistant to chemotherapy and radiation.
By targeting ATDC, we may be able to make cancer cells more sensitive to the therapies we already have in hand. Efforts to develop new therapeutics targeting ATDC are underway.
ATDC also appears to be critical to the function of other cancer types, including bladder cancer and lung cancer. We are continuing to investigate the biological function of ATDC in those cancers.