Linking Two Seemingly Unrelated Diseases, Cancer and Acute Respiratory Distress Syndrome, Through a Dictyostelium Secreted Protein

Abstract

The work in this dissertation links two diseases through a protein secreted by Dictyostelium discoideum cells. The protein, AprA, inhibits cell proliferation and induces chemorepulsion (movement away) of Dictyostelium cells. This has implications in both cancer research and the study of Acute Respiratory Distress Syndrome.

Cancer is a misregulation of cellular proliferation. Often the removal of a primary tumor results in rapid metastatic cell proliferation. The rapid proliferation of metastatic cells indicates the presence of a factor, called a chalone, secreted by the primary tumor cells, that inhibits metastatic cell proliferation. The ability of AprA to inhibit proliferation of the cells that secretes it classifies it as a chalone. Using the model organism Dictyostelium and the protein AprA allows us to study chalone signaling mechanisms.

Acute Respiratory Distress Syndrome (ARDS) is characterized by an excess influx of neutrophils into the lungs. Neutrophils damage the lung tissue and ultimately recruit more neutrophils that repeat the process. A need exists to remove these cells and allow resolution to occur. One way to accomplish this is through chemorepulsion, the directional movement of cells away from an external cue. We can use AprA to study the mechanisms of chemorepulsion.

In this dissertation, I have found that the PTEN-like protein CnrN, which is an inhibitor of proliferation and chemotaxis, is involved in both AprA proliferation inhibition and chemorepulsion of Dictyostelium cells. I have shown that the human protein DPPIV, which is structurally similar to AprA, causes chemorepulsion of human neutrophils. Additionally, aspirated DPPIV reduces the accumulation of neutrophils in the lungs of a mouse model of ARDS. Work shown in the appendices suggests that AprA signals through specific G protein-coupled receptors.

The work in this dissertation studies the role of chalones and chemorepellents. It allows the unique opportunity to study chemorepulsion in both Dictyostelium and human cells. The hope and goal is that the work in this dissertation could lead to novel therapies for diseases such as cancer and ARDS.