Defining the role of absent in melanoma 1 (AIM1) in aggressive prostate cancer
Abstract
Cancer’s most feared feature is its ability to invade into benign tissues and spread to distant sites. Prostate cancer, for instance, can travel to any part of the body, most commonly to lymph nodes and bones where it is very challenging to treat. To intercept the process of cell invasion and metastasis formation with new therapies, we need to understand how tumor cells migrate and spread through the body. Every cell has a structural scaffold, a skeleton termed the cytoskeleton. It consists of a complex interlinked network of proteins that supports the cell and helps maintain its shape. To invade other tissues, cancer cells need to alter their cytoskeletal properties to become malleable enough to change their shape and move through tissues. However, the process by which cancer cells become such “shape shifters” is not well understood. We have recently unmasked an important protein, named AIM1, that regulates the cytoskeleton in benign cells and is dysfunctional in cancer. When AIM1 is present, the cells’ scaffolding keeps it rigid and correctly shaped. When AIM1 is lost, cells can remodel their cytoskeleton more frequently to change their shape and become capable of invading and migrating to distant locations. Notably, in preliminary studies, we find that the AIM1 gene is frequently lost or mutated in aggressive forms of prostate cancer. We therefore hypothesize that, by losing AIM1, prostate cancer cells gain the ability to change shape, migrate, invade, and spread to different tissues. In this proposal, we will take a closer look at the relationship between the cytoskeleton, cancer cell invasion, and metastasis formation. In particular, we want to understand exactly how AIM1 controls the cytoskeleton and keeps cells from moving. We will study how AIM1 function is corrupted in human prostate cancer and use this information to generate a model of aggressive prostate cancer in mice. This will allow us to determine why tumors with corrupted AIM1 function are so aggressive. The final goal of this research is to develop new and innovative therapies that allow us to specifically target cancers with dysfunctional AIM1. To this end, we will perform a cutting-edge genetic screen that unmasks vulnerabilities in cancer cells that can be used as novel drug targets. Prostate cancer is a devastating disease, and there is a great need for better therapies. The work proposed here will provide important information about how cancer cells can become “shape shifters,” allowing them to invade and spread to other organ sites. We will use these insights to explore vulnerabilities in invasive cancer cells to intercept their lethal trajectory. This could ultimately lead to a novel class of therapies to treat aggressive prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010111
Entities
People
- Michael C. Haffner
Organizations
- Fred Hutchinson Cancer Center
- United States Army