Functional Analysis of E-Cadherin in Prostate Cancer Progression

Training Plan: My primary career goal is to understand the genetic changes that occur within cells of the prostate when they become cancerous and how this information can be used to develop cancer therapies. As a member of Dr. Michael Shen's lab in the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University Medical Center, I aim to achieve this goal through the use of mouse models of prostate cancer. The Shen lab offers a rich intellectual environment for education and training to meet this goal, particularly since its work to date has significantly improved the understanding of how cancer begins and progresses in the prostate. My training plan includes the following: individualized mentorship by Dr. Michael Shen that includes rigorous training in molecular and cell biology techniques and mouse genetics, scientific writing, formal research presentations, lab meetings to discuss progress of projects and relevant journal publications, participation in seminars and workshops that brings together scientists from different fields at the HICCC at Columbia University. In the current project proposal, I will study tumors that have lost E-cadherin, a tumor suppressor gene, during mouse prostate cancer progression. The ultimate goal to establish whether mouse prostate cancers that lose E-cadherin are more aggressive and to ask if they show features of prostate cancer invasion and metastasis similar to human prostate cancer. Hence, I believe this project will be crucial in my development as an independent scientist and in contributing to understanding the biology of prostate cancer.

Research Plan:

Rationale: Metastasis is the process by which cancer spreads from the place at which it first arose as a primary tumor to distant locations in the body. Metastasis depends on the cancer cells acquiring the ability to move. While much of cancer research so far has focused on identifying the genetic changes that transform normal cells into cancer cells, little is known about genetic changes that cause cancer cells to undergo metastasis. The main reason for this is that advances in diagnostic and surgical technologies have provided us with samples of human cancer cells at the primary site. However, to understand metastasis, we need techniques that will allow us to follow the cancer cells as they move to secondary sites. This is made complicated by the fact that the genetic changes are stochastic in nature and the number of such metastasized cells is very small. The first step of metastasis is cancer cells leaving their primary tissue, most likely aided by a change in cell behavior that makes them more motile. This change in cell behavior is associated with disruption of certain genes and activation of other genes, a process termed epithelial-mesenchymal transition (EMT). One of the earliest genes disrupted is E-cadherin, producer of a cell adhesion protein that ensures cells make proper contacts with one another. It has been shown that when E-cadherin is disrupted in cancer cells grown in a dish, they show invasive properties. It has also been shown that in human prostate cancer, tumors lose E-cadherin as they progress to advanced stages. But it has yet to be determined whether E-cadherin loss is a consequence or cause of invasion and whether E-cadherin loss in vivo (i.e., inside a living organism, like a human or a mouse) can cause EMT. These questions can be best addressed by using a genetic technique in which cells that lack E-cadherin are marked by a fluorescent protein throughout their lifetime, allowing them to be studied at different stages of cancer progression in vivo. This technique also has the advantage of studying cells in their natural environment instead of a dish, which is known to alter their properties.

Objective: The prevailing wisdom is that EMT confers migratory properties to cancer cells that enable their metastasis. The overall objective of this project is to examine whether removing E-cadherin in cancer cells plays a role in EMT and in prostate cancer invasion in vivo. We will use a genetic approach to study E-cadherin loss in a mouse model of prostate cancer to answer the following questions: (1) Does E-cadherin loss in tumor cells affect their cell behavior? (2) What are the genes affected by E-cadherin loss? (3) Can restoring these genes restore the cell behavior prior to E-cadherin loss?

Outcomes and Applicability: I anticipate that this project will have a direct impact on assessing the genes that affect prostate cancer metastasis and hence should lead to important insights into distinguishing indolent from aggressive prostate cancer. Therefore, my studies address the area of Tumor Biology. Finally, if E-cadherin loss affects tumor progression, it will be valuable to determine whether genetic pathways altered by its loss may represent therapeutic targets for what is presently considered to be untreatable end-stage disease.