Feedforward Signaling Between Glia, Neurons, and Mast Cells Contributes to Polyp Formation and Growth

Principal Investigator: LINDEN, DAVID R
Institution Receiving Award: MAYO CLINIC
Program: PRCRP
Proposal Number: CA170468
Award Number: W81XWH-18-1-0218
Funding Mechanism: Idea Award with Special Focus
Partnering Awards:
Award Amount: $616,850.00


Topic Area: Colorectal Cancer

Military Relevance Focus Area: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.

Scientific Objective and Rationale: We are beginning to understand more and more that the area around tumor cells, or microenvironment, contributes greatly to disease progression. We know that immune cells, especially a particular type called mast cells, contribute signals to the microenvironment and to tumors that can affect disease progression. The microenvironment also contains the endings of nerve cells called nerve fibers, and related supportive cells called glia. Nerves control normal bowel function and provide a two-way link between the bowel and the central nervous system. We are beginning to understand that glia may also be actively involved in signaling within the nervous system, rather than just providing structural support. Several observations have been made that nerves grow into colorectal cancers and that this nerve growth is associated with greater progression and increased mortality of the disease. This provides a strong rationale to better understand nerve cells in colorectal cancer. What is not known is what the signals are from colorectal tumors that cause increased nerve growth and whether, or how, the nerves directly affect disease progression. This proposal seeks to address both of these gaps in knowledge by testing the hypothesis that feedforward signaling between glia, neurons, and mast cells contribute to polyp growth. We will use a mouse model of colorectal cancer that is based on the gene that is most commonly mutated in colorectal cancer, APC. We will use new genetic approaches to directly and definitively test the role of new potential signals that can cause nerve growth and to test whether nerve activity is responsible for polyp growth in the mutant APC mouse.

Applicability of the Research: The results of the proposed studies will have a significant impact on colorectal cancer research and quite potentially future diagnostic or therapeutic care for patients with colorectal cancer. Finding new cell types and new molecules that contribute to colorectal cancer progression will open new avenues for therapeutic discovery. In addition, a mechanistic understanding of how glia and nerve cells contribute to colorectal cancer could help care workers more quickly adopt newer, more precise diagnostic tools or therapies. Thus, this proposal has the potential to significantly impact patient care.

Relevance to Active Duty Service Members, Veterans, and Other Military Beneficiaries: Colorectal cancer is the third most deadly cancer for both the general public and military beneficiaries. Thus, a better understanding of how nerves contribute to disease progression has the potential to impact all patients with colorectal cancer. Nerve cells provide the link between the central nervous system (CNS) and the bowel. Because there is a higher incidence of chronic stress and depression in military beneficiaries compared to the general public, and these disorders of the CNS have the ability to impact bowel function through the nerve cells the reach the bowel, there is potential that a greater understanding of how nerve cells contribute to colorectal cancer could have a more significant impact on military beneficiaries than the general public.