Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a high frequency of key driver mutations, (e.g. KRAS, TP53, CDKN2A, and SMAD4), as well many less frequent driver mutations. PDAC overexpresses growth factors such as TGF-?s, growth factor receptors including the EGF receptor (EGFR), a markedly desmoplastic stroma, and a propensity to develop metastases and chemoresistance. The 5-year survival rate for PDAC is 8-9% with current therapeutic modalities such as gemcitabine plus nab- paclitaxel or FOLFIRINOX. There is an urgent need, therefore, to devise novel therapies in PDAC. High microRNA-10b (miR-10b) levels in the cancer cells from PDAC tissues are associated with decreased patient survival and earlier appearance of metastatic disease following neoadjuvant radiochemotherapy. miR-10b targets the 3'UTR of tat-interacting protein 30 (TIP30) and downregulates TIP30 mRNA levels. Data from The Cancer Genome Atlas (TCGA) revealed that TIP30 is frequently altered in human PDAC cases. When combined with human PDAC cases overexpressing miR-10b together with cases containing loss of TIP30 then ~80% of cases in the UTSW dataset contain alteration of the TIP30 pathway. The effect of TIP30 loss in PDAC is not fully understood. In this proposal we will use a novel genetically engineered mouse model with oncogenic Kras and Tip30 deficiency (KTip30C) to assess novel molecular mechanisms of pancreatic cancer cell (PCC) signaling and metastasis induced by Tip30 loss. Our preliminary results indicate that KC mice with heterozygous loss (hetloss) of Tip30 develop pulmonary metastasis while KC mice with homozygous loss of Tip30 develop liver metastasis. PCCs with heterozygous loss of Tip30 also have increased EGFR levels. These preliminary data will allow us to test the hypothesis that heterozygous loss of Tip30 prevents efficient EGFR degradation, leading to upregulation of EGFR and accelerated lesion progression to murine PDAC and metastasis. We will evaluate the role of Tip30 hetloss in EGFR trafficking and elucidate the mechanism of Tip30-hetlloss mediated PCC pulmonary metastasis. We will use cell lines established from this model to perform colocalization and next-generation sequencing studies, and an orthotopic model using KTip30C PCCs to uncover the mechanism of Tip30 hetloss PCC metastasis to the lung. The results of these studies will allow for a broader understanding of pancreatic cancer metastasis and delineate the molecular actions of TIP30 in PDAC.
Pancreatic ductal adenocarcinoma (PDAC), a highly metastatic disease, is predicted to become the second leading cause of cancer-related deaths by 2020-2030. The discovery of novel mechanisms of PDAC pathogenesis and metastasis, which is proposed in this research plan will help advance the field and contribute to improving patient care. TIP30 is genetically altered in 49% of human PDAC, but its role has not yet been fully elucidated in the context of PDAC.
