FEEDFORWARD SIGNALING BETWEEN GLIA, NEURONS, AND MAST CELLS CONTRIBUTES TO POLYP FORMATION AND GROWTH

Project: Research project

Project Details

Description

Background: While significant advancements have been made in our understanding of stepwise progression of genetic mutations that contribute to colorectal cancer, as well as the role of tumor microenvironment including mesenchymal and immune cells to the initiation or progression of disease, colorectal cancer remains a common, deadly disease. The gap in care for colorectal cancer arises from the slow and insidious course of the disease with delays in detection and treatment until an advanced stage where current knowledge fails to identify targets to reverse tumor progression. Nervous signals have recently emerged as critical determinants of the microenvironment that promotes cancer progression in prostate, pancreatic, skin, and gastric cancers. Intestinal innervation is complicated with different classes of neurons contributing to normal digestive function. While increased innervation has been observed in colorectal cancer, the signals that cause this, and whether the nerves contribute to colorectal cancer progression remain unclear. Numerous enteric neurotranmitters recruit and activate mast cells that are known to advance cancer progression. Our innovative hypothesis is that rather than distinct, parallel environmental contributors to disease, neural invasion and mastocytosis are part of a single, connected, feed-forward mechanism of colorectal cancer progression.Objective: Determine signal mechanisms that contribute to increased innervation, mastocytosis and polyp growth.Hypothesis: Feedforward signaling between glia, neurons, and mast cells contribute to polyp growth.Specific Aim 1: Determine signals to enteric glia and neurons that contribute to increased nervous innervation of polyps and polyp growth.Specific Aim 2: Determine the role of neural activity in mastocytosis and polyp growth.Study Design: Hereditary APC mutant mice crossed with Cre/ERT2-inducible transgenic mice will be used to target-specific cell types and precise molecular targets suspected of causing gliosis, enhanced innervation, and polyp growth. For both specific aims, polyp number and size will be measured as a primary outcome of intervention. In Specific Aim 1, we will also use immunohistochemistry and 3D confocal microscopy of whole thickness intestinal segments to determine changes in glia and nervous innervation. We will knock out Evi/GPR177 from epithelial cells, MyD88 from enteric glia, and Ret from enteric neurons. In Specific Aim 2, we will chronically reduce nerve activity chemogenetically by expressing the inhibitory DREADD hM4Di and administering the normally inert drug clozapine-N-oxide (CNO). In addition to polyp measurements, we will use flow cytometry and immunohistochemistry to quantify mast cells and determine the proximity of nerves to mast cells.Innovation: The hypothesis is innovative, and we employ novel, innovative technologies to definitively test our hypotheses providing results that advance our understanding of nervous innervation in colorectal cancer regardless of the findings. Thus, the proposed studies will provide a significant, rather than incremental, advance in our understanding of the nervous system in colorectal cancer.Military Relevance: This proposal seeks to address the 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. Specifically, we aim to directly address the gap in knowledge regarding the role of nervous innervation in colorectal cancer. The altered nervous system states of military beneficiaries including acute and chronic stress and depression may disproportionately contribute to colorectal cancer progression in this population compared to the general public. The proposed studies may provide the mechanistic link between nerves, mast cells, and cancer.

StatusFinished
Effective start/end date7/1/186/30/20

Funding

  • Congressionally Directed Medical Research Programs: $616,850.00

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