Metastatic Breast Cancer: Examining the Role of the Tumor Microenvironment
Maja Oktay, MD, PhD, studies breast cancer microenvironments responsible for metastasis as well as the effect of chemotherapy on the tumor microenvironment as it relates to metastasis. In particular, the Oktay laboratory focuses on the function of breast cancer intravasation sites called TMEM (Tumor MicroEnvironment of Metastasis) and its interactions with pro-metastatic Mena-expressing tumor cells. Using fine needle aspiration (FNA) biopsy-obtained breast cancer cells from patients, Dr. Oktay determined that cancer cell dissemination markers MenaINV and MenaCalc correlate with TMEM score in estrogen-positive and triple-negative breast cancers from patients, indicating mechanistic involvement of MenaINV, and MenaCalc in TMEM assembly and function in human breast cancer.
In addition, using FNA-obtained cancer cells from patients for functional in vitro trans-endothelial migration studies, Dr. Oktay demonstrated that TMEM sites and MenaINV expression in cancer cells are essential for cancer cell trans-endothelial migration in all clinical subtypes of breast cancer. She also participated in the prospective validation study which demonstrated that TMEM score is a predictive marker of metastasis in breast cancer patients, and in a study which demonstrated that TMEM sites are functional sites of transient blood vessel permeability and, as such, the only sites of breast cancer cell intravasation. Dr. Oktay also led a study which established that commonly used chemotherapy for breast cancer can induce TMEM and MenaINV mediated pro-metastatic changes in breast cancer in the neoadjuvant setting, and demonstrated that these changes can be reversed by Tie2 inhibition.
Investigating Potential New Treatment Strategies for Late-Stage Breast Cancer
Rachel Hazan, PhD, studies cadherin adhesion molecules and their role in metastatic breast cancer.
Aiming to expand the available options for treating late-stage breast cancer, the Hazan laboratory is investigating: 1) the molecular basis for cooperation between N-cadherin and the FGF receptor responsible for epithelial to mesenchymal transition (EMT) and metastasis with the goal of obtaining functional inhibitors of metastasis; 2) regulation of EMT and metastasis by the MAPK and AKT signaling pathways; 3) the relationship between cell cycle progression and tumor metastasis; 4) the mechanism of HER2 therapeutic resistance in breast cancer; and 5) cancer stem cells and their role in breast cancer metastasis.
Dr. Hazan and her team have shown that N-cadherin, a cadherin involved in dynamic processes such as cell migration and neurite outgrowth, is upregulated in invasive breast cancer cells and promotes metastasis of breast cancer cell lines. In contrast, E-cadherin, known to promote stable epithelial contacts, is lost during metastatic progression. Their data suggest that the shift in cadherin expression also affects proteolytic activity of cells, their migration, invasiveness and metastasis.
More recently, they discovered that Retinal cadherin (R-cadherin), a classic cadherin highly expressed in the brain and retina, is also present in the mammary epithelium. They showed that: 1) like E-cadherin, R-cadherin acts as an invasion-suppressor gene that is downregulated in invasive duct carcinomas; 2) R-cadherin knockdown in mammary-gland tissue leads to disruption of morphogenesis and gain of metastatic properties; 3) conversely, R-cadherin expression in aggressive tumor cells suppresses invasion and metastasis, and restores glandular morphogenesis.
Understanding the Role of Genetic Variants in Human Disease
Genetic differences play an important role in normal human development and disease. These differences can also play a role in the progression of disease and in individual responses to therapy. The laboratory of Harry Ostrer, MD, uses modern genomics to elucidate the roles of human genetic variation in these processes.
Dr. Ostrer and his team have developed functional variant assays to understand the phenotypic effects of genetic variants.
Genetic variation in human populations. The Ostrer Laboratory has characterized genetic variation in a number of human populations (Hispanics and Latinos, Jewish HapMap Project) to understand the origins and migrations of these populations. Currently, the investigators are exploring the role of natural selection in the formation of some of these populations in order to understand their disease susceptibilities. A key feature of this work is translating new findings into clinical practice to promote personalized medicine.
Human developmental disorders. Dr. Ostrer and his colleagues study the genetic basis of rare genetic disorders, notably disorders found in isolated populations and disorders of sex development, to identify both the mutational basis and the molecular mechanisms. Recently, they identified mutations in genes in the MAP kinase pathway in abnormal testicular development and now are investigating the roles of members of this pathway in normal testicular development.
Cancer genetics and genomics. The Ostrer Laboratory has explored the roles of low- and high-penetrance variants in risk of human cancers, and has developed models for predicting risk. Through genome-wide association studies, the investigators have identified common variants that increase the risk of adverse outcomes (erectile dysfunction, urinary dysfunction, proctitis) for men treated with radiation therapy for prostate cancer. The investigators have developed a molecular signature based on acquired somatic copy-number alterations that is highly predictive of risk of metastasis and may account for the increased risk among African-American men. A similar model is being developed for breast cancer.
Head and Neck Cancer Research Program
Beginning over 20 years ago, a group of basic science faculty at Einstein, led by
Michael B.Prystowsky, MD, PhD,
initiated a collaborative effort with the clinical care team at Montefiore led by
Richard V. Smith, MD. The two teams joined forces to employ high-throughput genomic techniques established by
Geoffrey J. Childs,PhD,
to study Head and Neck Squamous Cell Carcinoma (HNSCC). Their goal: to develop new diagnostic and prognostic signatures to guide clinical decisions for optimal treatment and patient outcomes.
Current core group members include:
Michael B. Prystowsky, MD, PhD; Geoffrey J. Childs, PhD; Thomas M. Harris, PhD; Thomas J. Ow, MD; Jeffrey E. Segall, PhD; and Richard V. Smith, MD.
The group maintains a database of global gene expression, methylation and global proteomic data from about 500 head and neck tumors as a resource. The database is augmented by a linked clinical database that stores information on demographics, tumor characteristics, treatment, recurrence, survival, and other relevant clinical information and outcome measures from each patient they study. This database is an invaluable resource for the group’s translational research, which speeds the application of innnovative treatment strategies from the laboratory bench to the patient bedside.
One specific research focus is the role of miR-375, a micro-RNA, in modifying tumor phenotypes. The investigators decided to pursue this line of inquiry based on their finding that lower levels of miR-375 are associated with decreased disease-specific survival and increased recurrence, and seem to increase invasive properties of head and neck cancer cells. The targets of this micro-RNA and their role in making tumors more invasive and less sensitive to ionizing radiation are being studied. The investigators are exploring the potential use of miR-375 as a nucleic acid therapeutic agent for HNSCC.
There is always a need to develop more-effective chemotherapies based on mutations and pathways affecting tumor survival and growth. Dr. Thomas J. Ow, a surgeon-scientist, is currently investigating predictive biomarkers and molecular treatment targets in HNSCC. His recent work has focused on signaling molecules in the intrinsic apoptosis pathway and cell cycle regulators as potential biomarkers and treatment targets.