The long-term goal of our proposal is to elucidate the molecular mechanisms by which protein tyrosine phosphatase T (PTPRT) functions as a tumor suppressor. In a high-throughput mutational analysis, we identified PTPRT as the most frequently mutated phosphatase in human colon cancers. Recent exome sequencing studies uncovered that PTPRT is also mutated in lung, gastric, and ovarian cancers, in head & neck squamous cell carcinomas, and in melanomas. In the previous funding period, we demonstrated that Ptprt knockout (KO) mice are prone to develop colon cancer, thereby providing critical in vivo evidence to support the premise that PTPRT functions as a tumor suppressor. Using a cutting-edge phospho-proteomic approach, we identified STAT3 and paxillin as PTPRT substrates. PTPRT dephosphorylates the key STAT3 activation site Y705. Our preliminary studies showed that, compared to wild-type littermates, intestinal stem cells in Ptprt KO mice are more proliferative and that pY705 STAT3 is up-regulated in the intestinal stem cell compartments of Ptprt KO mice. In light of recent exciting studies by others demonstrating that intestinal stem cells are the origin of intestinal tumors, we will determine in Aim 1 how PTPRT regulates intestinal stem cell homeostasis and whether PTPRT-regulated STAT3 signaling plays a critical role in intestinal stem cell homeostasis and the in vivo tumor suppressor function of PTPRT. In addition, PTPRT dephosphorylates a previously unstudied paxillin phospho-tyrosine site, Y88 (pY88). We found that pY88 paxillin is up-regulated in a majority of human colon cancer specimens. Interestingly, our preliminary studies showed that very high levels of pY88 paxillin associate with advanced-stage colon cancers, suggesting that pY88 paxillin may be exploited as a prognostic biomarker. Moreover, we engineered paxillin Y88F mutant knock-in colon cancer cell lines and demonstrated that they exhibit reduced tumor formation in vitro and fail to form xenograft tumors in nude mice. Together, our studies suggest that pY88 paxillin mediates pivotal oncogenic signaling in colon cancer.
In Aim 2, we will focus on elucidating the mechanisms by which pY88 paxillin signaling promotes oncogenesis.
In Aim 3, we will determine if the PTPRT-regulated pY88 paxillin pathway can be exploited as a prognostic marker for colon cancer. Success in these studies will result in delineation of novel mechanisms underlying intestinal stem cell homeostasis and colon tumorigenesis, provide a novel prognostic tool to guide clinical management of this deadly disease, and define a potentially important new therapeutic target. Because PTPRT is mutated in multiple human cancers, knowledge gained from these studies may have broad implications for cancer therapy.
Colorectal cancer is the second most common cause of cancer deaths in the United States, with 150,000 new cases and 55,000 deaths per year. Advances in understanding the molecular pathogenesis of this disease are fundamental to our understanding of cancer development and successful clinical intervention. Our proposed studies will delineate novel mechanisms underlying colon cancer development, define novel therapeutic targets, and search for new prognostic tool to guide clinical management of this deadly disease.
|Hu, Xiao; He, Yanhua; Wu, Liping et al. (2017) Novel all-hydrocarbon stapled p110?[E545K] peptides as blockers of the oncogenic p110?[E545K]-IRS1 interaction. Bioorg Med Chem Lett 27:5446-5449|
|Zhao, Yiqing; Scott, Anthony; Zhang, Peng et al. (2017) Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis. Oncotarget 8:48782-48793|
|Hao, Yujun; Samuels, Yardena; Li, Qingling et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971|
|Peyser, Noah D; Wang, Lin; Zeng, Yan et al. (2016) STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma. Cancer Prev Res (Phila) 9:657-63|
|Wang, Zhenghe; Li, Li; Guda, Kishore et al. (2016) Adverse Clinical Outcome Associated With Mutations That Typify African American Colorectal Cancers. J Natl Cancer Inst 108:|
|Merry, Callie R; Forrest, Megan E; Sabers, Jessica N et al. (2015) DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet 24:6240-53|
|Guda, Kishore; Veigl, Martina L; Varadan, Vinay et al. (2015) Novel recurrently mutated genes in African American colon cancers. Proc Natl Acad Sci U S A 112:1149-54|
|Fink, Stephen P; Myeroff, Lois L; Kariv, Revital et al. (2015) Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. Oncotarget 6:30500-15|
|Zang, Wenwen; Hao, Yujun; Wang, Zhenghe et al. (2015) Novel thiourea-based sirtuin inhibitory warheads. Bioorg Med Chem Lett 25:3319-24|
|Zhao, S; Sedwick, D; Wang, Z (2015) Genetic alterations of protein tyrosine phosphatases in human cancers. Oncogene 34:3885-94|
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