Modeling and Targeting Metastatic Drivers Identified in Sleeping Beauty Screens and Coding for Cytoplasmic Signaling Proteins
Abstract
Breast cancer mortality is caused by the spread of tumor cells to other parts of the body (metastases) such that surgery alone cannot stop disease progression. These metastases usually grow in the lung, bone, liver, and even brain, causing great pain. They ultimately interfere with the normal functions of these vital organs, leading to death. One of the greatest challenges in breast cancer research is to understand mechanisms that lead to cancer moving away from the primary tumor, taking root in other tissues. Indeed, if we could understand what drives this process, then we could start to design rationale therapies to effectively prevent and treat metastases. This is a daunting challenge because access to metastases is limited. Metastases are rarely even removed by the surgeon for ethical reasons since such an operation is unlikely to benefit the, now very sick, patient. Instead, chemotherapy is used to contain their growth. This almost invariably fails, leading to death within 1-5 years after metastatic disease is first detected. These difficulties in even obtaining tissue for study means that most of what we know about breast cancer is based on knowledge gained from study of the primary tumor, as it sits within the breast. The Egan and Zacksenhaus labs have taken a new approach to the study of metastatic breast cancer. Specifically, we have taken advantage of a recently developed cancer gene discovery system that is based on transposons, also known as "jumping genes." Such approaches helped us to find the genes driving metastasis because when the transposon jumped into a "metastasis gene" and thereby caused the tumor to spread to another organ, it left a tag or mark at that gene, which we could use to find it. Thus, we activated transposon jumping in transgenic mice that were already programmed to developed breast cancer. The transposons would, at a low frequency, jump into metastasis genes and thereby cause the tumor to spread. Indeed, this happened as predicted, and we surgically removed the lung and liver metastasis on autopsy of tumor-bearing mice. Finally, we used the transposon tag to find marked metastasis gene(s). Using such transposon screens, we identified several genes that promote metastatic spread of breast tumors. These genes control two types of biological processes: one that allows cancer cells to survive stress, such as low oxygen or nutrient deprivation, and another that allows cells to become motile and invade surrounding tissues. We will now test and validate the effect of these genes on metastatic dissemination of non-aggressive human breast cancer cells that have limited capacity to disseminate after they are injected into the mammary gland of immune-deficient mice. We will also test for the importance of these genes in aggressive human breast cancer cells that readily metastasize. We will study the specific stages in which these genes are critical for metastasis, for example, in the invasion into surrounding tissue, survival in the blood stream, or growth of tumor cells in lungs or other organs. Finally, we will initiate a drug-screening program to find inhibitors of our identified pro-metastatic genes and test these drugs as potential new therapy to prevent or treat metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610048
Entities
People
- Eldad Zacksenhaus
Organizations
- United States Army
- University Health Network