Graduation Date

Spring 5-6-2017

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biochemistry & Molecular Biology

First Advisor

Rakesh K. Singh


Pancreatic cancer (PC) is an aggressive disease with an overall 5-year survival rate of less than 7%, statistics that have not changed in almost five decades. Metastasis is one of the leading causes of mortality in PC. Accumulating evidence suggests that axon guidance molecules, such as semaphorins, are involved in cancer progression, invasion, and metastasis. Recent genomic characterization of pancreatic ductal adenocarcinoma revealed aberration in axon guidance pathway genes as well. Previous reports from our laboratory have identified one such molecule Semaphorin5A (SEMA5A) as a putative cell adhesion molecule which is involved in organ-specific homing during PC metastasis. My dissertation work “The Role of Semaphorin 5A in Pancreatic Cancer progression and metastasis” investigates the pathological significance and functional role of SEMA5A during pancreatic cancer progression and metastasis. The expression of the SEMA5A in human pancreatic cancer tissue and metastatic sites as well in different pancreatic cancer progression models of Pancreatic Ductal Adenocarcinoma as well as Pancreatic Neuroendocrine Tumors was analyzed. This study has identified upregulation of SEMA5A in pancreatic tumors as well as metastases in comparison with the normal pancreas. Furthermore, we examined the functional role of SEMA5A and demonstrated that the upregulated and secretory form of SEMA5A increase pancreatic cancer cell migration as well as enhance metastasis by acting as a ligand for Plexin B3 receptor. We have also shown that SEMA5A increase pancreatic cancer cell migration by activating Met tyrosine kinase receptor.

In addition, we made an attempt to understand the function of endogenous SEMA5A expression in a pancreatic cancer cell by generating knockdown of SEMA5A in different pancreatic cancer cell lines. Interestingly, we observed that loss of SEMA5A increases cellular migration and enhanced metastasis by inducing Epithelial to Mesenchymal Transition (EMT). Furthermore, we demonstrate that upregulation of TGF-b2 secretion and non-canonical activation of PI3K-AKT signaling may mediate this transition. Similar to loss of SEMA5A, knockdown of Plexin B3 also induces mesenchymal phenotype and enhances metastasis though not by inducing EMT. Together, these data demonstrate that SEMA5A/Plexin B3 axis may play a significant role in maintaining an epithelial state of pancreatic cancer cells that limits the invasive capabilities of these cells.

Overall, the results presented in this dissertation reveal that SEMA5A signaling can mediate both tumor-promoting roles by enhancing cellular migration and angiogenesis and tumor inhibitory effects by maintaining epithelial phenotype and keeping invasion under check.