Loss of TIP30 Accelerates Pancreatic Cancer Progression and Metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the United States, and is characterized by key driver mutations (e.g. KRAS, TP53, CDKN2A, and SMAD4), elevated expression of growth factors such as TGF-βs and the EGF receptor (EGFR), a markedly desmoplastic stroma, and a propensity to develop multi-organ metastases and chemoresistance. Consistent with its aggressive nature, the 5-year survival rate for PDAC is 8-9%, which demonstrates an urgent need to develop novel therapies. High expression levels of microRNA-10b (miR-10b) in PDAC tissues are associated with decreased patient survival and earlier appearance of metastatic disease following neoadjuvant chemoradiotherapy. miR-10b downregulates the expression of transcription coactivator Tat-Interacting Protein 30 (TIP30) by targeting its 3’UTR. TIP30 has multiple reported functions. TIP30 suppresses tumor formation and metastasis, forms a complex that regulates EGFR trafficking and degradation, and transcriptionally upregulates pro-apoptotic genes. Alterations in TIP30 have been reported in multiple human cancers, including pancreatic cancer. We hypothesized that Tip30-deficiency accelerates PDAC progression and metastasis in a murine model of PDAC. To test this hypothesis, we crossed mice with oncogenic Kras (KC) localized to the pancreas epithelium, with Tip30-deficient mice (K30C). We compared PDAC histopathology between Tip30-heterozygous (K30+/-C) and Tip30-null (K30-/-C) mice. Tip30-heterozygosity accelerated PDAC-lesion-associated pancreatic cancer cell (PCC) pulmonary seeding. By contrast, total loss of Tip30 enhanced PCC micrometastatic seeding to the liver and hepatic metastasis. K30+/-C mice also presented with an early, increased penetrance of lung lesions and lung adenocarcinoma; and PCCs isolated from K30+/-C pancreata exhibited increased EGFR protein levels. These findings suggest that TIP30 deficiency can have a dose-dependent effect on organotropic metastasis and EGFR levels in PCCs. Future studies will delineate the molecular consequences of TIP30 loss in PDAC and contribute to a broader understanding of pancreatic cancer metastasis.