Functional Validation of Pancreatic Cancer Progression Biomarker

Abstract public domain (NIH RePORTER)

Project Abstract/Summary Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Functional identification and validation of progression biomarkers is essential for pancreatic cancer diagnosis and treatment. Recent studies indicated that the aberrant Wnt/¿-catenin pathway activation in pancreatic cancer cells play an important role in cell proliferation, invasion, and metastasis. Stability and nuclear translocation of ¿-catenin protein is a critical step leading to malignant phenotype of pancreatic cancer. Our recent studies also have shown that transcription factor FoxM1 critically contributes to cell proliferation, invasion and tumorigenicity of human pancreatic cancer. Importantly, our studies have shown that FoxM1 and ¿-catenin appears to be associated with each other physically and functionally in pancreatic cancer cells. The prior studies including our own are sufficient to make us believe that the interactions between FoxM1 and ¿-catenin signaling play a critical role in pancreatic cancer development and progression. To test our hypothesis, we have designed several sets of experiments organized around three specific aims with well-defined goals. Aim 1 will determine whether FoxM1 interacts with ¿-catenin and promotes its nuclear translocation; Aim 2 will define the role of the interaction of ¿-catenin/FoxM1 in pancreatic tumor invasion and metastasis; and Aim 3 will to determine the expression of ¿-catenin and FoxM1 in pancreatic cancer tissues and delineate their clinical significance in human pancreatic cancer pathogenesis. Thus, our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology. Completion of our proposed studies will represents a substantial advance in our understanding the in-depth mechanism of dysregulated ¿-catenin and FoxM1 expression and function in general and in pancreatic cancer development and progression in particular. Thus, our proposed studies are fundamentally important to understand the interaction between ¿-catenin signaling and FoxM1 signaling and its function impact on pancreatic cancer biology and to determine its value as a molecular target for designing effective modality to control pancreatic cancer cell growth, invasion and metastasis. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated Wnt/¿-Catenin signaling and its crosstalk with FoxM1pathway. Translation of our findings into clinical patient care is another long-term goal of ours.

Public health relevance public domain (NIH RePORTER)

Project Narrative Crosstalk between ¿-catenin and FoxM1 signaling pathways and its impact on progressive growth and invasion of pancreatic cancer cells is unknown and our appealing evidence reveals a novel and significant research area of pancreatic cancer development and progression. Our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology. __SpecificAimsTextDelimiter__ B. SPECIFIC AIMS Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Functional identification and validation of progression biomarkers is essential for pancreatic cancer diagnosis and treatment. Recent studies indicate that the aberrant Wnt/¿-catenin pathway activation plays an important role in cell proliferation, invasion and tumorigenicity of pancreatic cancer cells. Our recent studies also have shown that transcription factor FoxM1 critically contributes to cell proliferation, invasion and metastasis of human pancreatic cancer. Importantly, our studies have shown that FoxM1 and ¿-catenin appear to be associated with each other physically and functionally in pancreatic cancer cells. These preliminary studies lead us to postulate that the interactions between FoxM1 and ¿-catenin signaling play a critical role in pancreatic cancer development and progression. To test our hypothesis, we propose the following three specific aims. Aim 1 will determine whether FoxM1 interacts with ¿- catenin and promotes its nuclear translocation; Aim 2 will define the role of the interaction of ¿- catenin/FoxM1 in pancreatic tumor invasion and metastasis; and Aim 3 will to determine the expression of ¿-catenin and FoxM1 in pancreatic cancer tissues and delineate their clinical significance in human pancreatic cancer pathogenesis. The aims integrate three different levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology, thus addressing the causal mechanisms, functional validation, and clinical relevance of our proposed studies, respectively. All three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular basis of progressive growth, invasion, and metastasis of pancreatic cancer cells and for identification of molecular targets to design effective strategies to control this deadly disease. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated Wnt/¿- Catenin signaling and its crosstalk with FoxM1pathway, while translation of our findings into clinical patient care is another long-term goal of ours.