Indiana University-Purdue University Indianapolis (IUPUI) / 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. / 2020-08-05
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20227 |
| Date | 07 1900 |
| Creators | Imasuen Williams, Imade E. |
| Contributors | Hurley, Thomas, Harrington, Maureen, Herbert, Brittney-Shea, Nakshatri, Harikrishna |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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