MUC1 MEDIATED SIGNALING IN PANCREATIC DUCTAL ADENOCARCINOMA

1 online resource (185 pages) : PDF

2019

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.

doctoral dissertations

Biology

Ph.D.

Cancer
MUCL
Mucin
Pancreatic Cancer
Pancreatic Ductal Adenocarcinoma
TGF-Beta

Biology

Mukherjee, Pinku

Dréau, Didier
Grdzelishvili, Valery
Truman, Andrew
Vivero-Escoto, Juan

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2019.

This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). For additional information, see http://rightsstatements.org/page/InC/1.0/.

Copyright is held by the author unless otherwise indicated.

Grover_uncc_0694D_12035

http://hdl.handle.net/20.500.13093/etd:1905