Pancreatic Cancers Desmoplasia: The Possible Bridge Impending Nerve Infiltration and Neoplastic Escape

Principal Investigator: CUKIERMAN, EDNA
Institution Receiving Award: INSTITUTE FOR CANCER RESEARCH
Program: PRCRP
Proposal Number: CA140228
Award Number: W81XWH-15-1-0170
Funding Mechanism: Idea Award with Special Focus
Partnering Awards:
Award Amount: $531,685.00


The proposal's Topic Area is Pancreatic Cancer (PC) while the Military Relevance Focus is to fill PC research gaps; the known PC risk factors are heavily over-represented in military and Veteran populations.

PC is one of the most aggressive cancers in the first world. Depending on the severity of the disease at time of diagnosis, patients are estimated to only survive between 5 to 10 months. It is therefore not surprising that PC is currently the fourth leading cause of cancer deaths in the United States. Alarmingly, incidents in PC have been recently predicted to increase, as opposed to decrease, and the PC Action Network reports forecasts that PC will become the second leading cause of cancer deaths by 2020. Also very troubling is the fact that many of the recognized risk factors believed to predispose the general population to develop PC are factors that are unfavorably over-represented in military and Veteran populations and their immediate families. Among these are diabetes, obesity, smoking, excessive consumption of alcohol as well as of fatty and processed meats, chronic pancreatic disease (such as pancreatitis), and occupational exposures to given chemicals and radiation. There are two interesting particulars seen in PCs. First, PC cells are only about 10% of the tumor mass. The rest of the tumor mass is a very specific reaction of the pancreatic connective tissue that, in response to signals provided by the neighboring cancer cells, undergoes a reaction that is very similar to chronic fibrosis. Second, pathologists have documented that a noteworthy amount of nerves infiltrate the tumor mass and are apparently responsible for both the extreme pain that PC cancer patients endure and the capability of cancer cells to use these nerves as physical "trails" onto which they escape this organ and invade to distant locations during metastatic disease.

We have developed a model that uses connective tissue cells obtained from fresh surgical samples of PC patients that mimics its fibrotic component. Using this model, we questioned if there were any proteins that were over-represented in the fibrotic component vs. normal-looking pancreas. As a result, we identified two interesting nervous system proteins that are not normally expressed in healthy pancreas. One of these proteins, NOVA1, has recently been shown to regulate the expression of a specific form of the second protein, NetrinG1 (G1). The written literature suggested to us that the function of G1 in neural tissue is to stabilize nerve connections. Interestingly, it also known that PC cells produce factors that attract nerve extensions. Therefore, in this study, we will try to test the possibility that fibrotic NOVA1 regulates high levels of a specific form of G1, promoting the stability of cancer-recruited nerve extensions. This, in turn, could be the reason for the excruciating PC pain and for its peculiar and highly invasive nature.

We plan to use a collection of pathological PC samples for which we retrospectively know the treatments that the corresponding patients have undergone as well as their outcomes and more. The pathological samples will be stained to identify nerve, cancer, and fibrotic areas to question whether NOVA1/G1 expressions and locations correlate with patient particulars. We have developed computational means to specifically analyze these types of data using a batch-image approach. Also, we will use our culturing model, in the laboratory setting, to see if the fibrotic PC neighboring cells that express NOVA1/G1 indeed stabilize nerve extensions and facilitate PC cell escape. The model can withstand biochemical and genetic manipulation to these proteins with the goal of testing the projected cellular functions.

The short-term goal of this study will not only provide mechanistic clues of NOVA1/G1 in the PC neighboring areas and their proposed roles in PC escape via neural invasion, but it could confirm the suspected clinical relevance of these novel biomarkers. Also, if successful, the proposed project will render preliminary data needed for a more detailed future proposal, which can last 5 years, in which we will be able to not only more precisely dissect the pro-tumorigenic functions of NOVA1/G1, but in which we will conduct preclinical tests aimed for clinical interventions. These interventions could take place immediately after or perhaps even start during the subsequent above-mentioned 5 years.

The study has a high potential to specifically impact enrolled and retired military health as it has been shown that military service is associated with significant (in some cases ~90%) increased risk for PC deaths when compared to the general population. Since military personnel and retired Veterans bestow increased propensities to develop PC, a study such as the one herein proposed could withstand a noteworthy effect that will preferentially benefit this population. Finally, we strongly believe that every study proposing to close the gap in PC knowledge and that renders possible novel future PC therapeutics potentially conveys a significant level of overall impact.