MUC1 MEDIATED SIGNALING IN PANCREATIC DUCTAL ADENOCARCINOMA
1 online resource (185 pages) : PDF
University of North Carolina at Charlotte
In 2019, Pancreatic Cancer (PC) is the 3rd leading cause of cancer-related deaths in the USA with 94% dying within 5 years of diagnosis. 90% of PC is Pancreatic Ductal Adenocarcinoma (PDA), of which >80% overexpress a hypo-glycosylated form the membrane-bound glycoprotein of Mucin-1 (tMUC1). While overexpression of tMUC1 is associated with metastasis and poor prognosis, the mechanism remains unclear. Transforming growth factor-β1 (TGF-β) is a cytokine with dual functionality. Within normal cells and during early carcinogenesis, TGF-β1 functions as a tumor suppressor through the engagement of the TGF-β Receptor 1 (TGF-βRI) and the activation of the canonical Smad pathway. In contrast, during the later stages of cancer, TGF-β1 acts as a tumor promoter activating the non-canonical Erk1/2 pathway. We establish the mechanistic connection between tMUC1 and TGF-β signaling in PDA and hypothesize that tMUC1 is the switch that turns TGF-β1 from a tumor suppressor into a tumor promoter. We have shown a correlation between tMUC1 expression and TGF-β signaling within an exogenous tMUC1 model of PDA. We specifically tested the hypothesis that the tyrosine kinases present in the cytoplasmic tail of tMUC1 are signaling between tMUC1 and TGF-β1, thus leading to enhanced metastasis. Data reported here indicate that tMUC1 influences TGF-β signaling in an exogenous tMUC1 PDA model (Chapter 2) and in endogenous MUC1 PDA cells both in vitro and in vivo (Chapter 3). The data support tMUC1 as a promising biomarker for TGF-β mediated therapies.
CancerMUCLMucinPancreatic CancerPancreatic Ductal AdenocarcinomaTGF-Beta
Dréau, DidierGrdzelishvili, ValeryTruman, AndrewVivero-Escoto, Juan
Thesis (Ph.D.)--University of North Carolina at Charlotte, 2019.
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