Breast cancer is the most common malignancy in women worldwide and the leading cause of cancer related death. More than 1.2 million cases are diagnosed every year, affecting 10-12% of the female population and accounting for approximately 500,000 deaths per year worldwide. The primary cause of morbidity and mortality in women with breast cancer is metastasis, the spread of tumor cells to distant sites in the body to form secondary tumors subsequently. During metastasis, cells from the primary tumor undergo a transformation that enables them to break away from the primary tumor mass and crawl towards blood vessels. Some tumor cells enter the bloodstream and are delivered to distant sites in the body where the exit the bloodstream, infiltrate target organs and subsequently form secondary tumors. While conventional chemotherapy is the standard of care for most breast tumors, metastasis-capable cells often remain in the primary tumor site, or linger elsewhere in the body after treatment. Work in the Gertler lab is aimed at understanding the mechanisms that drive tumor cell invasion and metastasis so that drugs targeting those processes can be developed and administered in combination with current standard of care therapeutics.
Research in the Gertler laboratory is focused on how tumor cells communicate with their local microenvironment. This bi-directional signaling involves non-tumor cells that are recruited the tumor, such as cells from the immune system as well as cells already near the tumor. This signaling between tumor cells and their microenvironment causes changes both in the tumor cell and in the cells present in the local microenvironment. Production and release of soluble signaling molecules in the microenvironment affects tumor cell survival, proliferation and the ability to invade surrounding tissue and migrate towards, and then enter the bloodstream. Other changes in the tumor microenvironment arising from bi-directional signaling include secretion and shaping of scaffolding proteins that comprise the extracellular matrix (ECM). ECM proteins can serve as pathways for cell movement, affect the stiffness of the tumor and can deliver signals to cells via specialized adhesion receptors known as integrins, or by binding to specific diffusible signaling proteins.
One aspect of the Gertler laboratory’s research focuses on a molecule called Mena that controls how cells move and respond to signals from the microenvironment. Mena performs multiple functions including controlling the assembly of F-actin, a structural protein that helps push the cell forward, and modulating signaling through alpha5beta1 integrin, a receptor that binds to the ECM protein fibronectin (FN) (see Figure 1). FN is one of the most abundant ECM proteins in the body, and accumulates at particularly high concentrations around blood vessels. During the past year, the Gertler laboratory has found that Mena is involved in helping cells detect FN and remodel FN from its soluble form into fibrils that are important for tissue integrity and stiffness.
Different forms of the Mena protein are generated by changes in the composition of the mRNA, that encodes the protein. These different forms of Mena are produced in cells at different points during breast cancer progression. “Mena11a” is produced by the normal epithelial cells in the ducts of the mammary gland, and is also found in primary tumors with a well organized, benign appearance. The Gertler lab has shown that patients with breast tumors containing a high fraction of Mena that is of he Mena11a form exhibit have significantly better odds of survival than patients with a low fraction of Mena11a in their tumors. During the last year, the Gertler lab has made substantial progress towards understanding how Mena11a exerts its anti-metastatic effects on breast cancer cells.
Highly aggressive, metastatic cells within breast tumors produce "MenaINV", which exacerbates metastasis by increasing cells cell movement and responses to soluble cues that guide tumor cell movement. Tumor cells that express MenaINV causes tumor cells to become extremely sensitive to a particular hormone, EGF, that activates the EGF receptor present on tumor cells to lure them into the bloodstream. During the past year, the Gertler laboratory has made substantial progress towards elucidating the mechanism underlying the pro-metastatic effects of MenaINV and have found that this form of Mena affects the amplitude of signaling by certain receptors on the cell surface. They have also found that MenaINV causes tumor cells to become resistant to certain types of targeted therapies used to treat cancer patients. This finding is particularly noteworthy because acquired resistance to therapy frequently leads to patient relapse after they have shown significant improvement in response to the targeted therapeutic.