Regulation of the angiogenic switch, Mechanisms of metastasis initiation and progression, The lung tumor microenvironment, Genome-wide analysis, RNA interference, Lung cancer and therapy.

Our scientific team harbors strengths in the areas of basic biology, bioinformatics and clinical applications. We are investigating the cellular and molecular mechanisms that dictate primary tumor growth, metastasis initiation and progression. Our approach is multidisciplinary in nature integrating strengths of functional genomic approaches to mouse genetic models of human cancer. A major aim is to rapidly confirm insights obtained from these investigations in preclinical and clinical settings, and determine the diagnostic and therapeutic potential of candidate molecules in cancer patients. A major focus of the laboratory is also to determine the contribution and biological role of bone marrow-derived microenvironments in these processes. The therapeutic potential of targeting these critical components is being carried out in collaboration with expert clinicians.
The main research focus areas are:

• Bone marrow-derived microenvironments as critical regulators of angiogenic switch.
• Therapeutic targeting of the bone marrow-derived microenvironment.
• Molecular mechanisms governing metastasis initiation and progression in the lung.
• Genome-wide analysis using massively parallel sequencing and RNAi library screens.

1. Role of bone marrow-derived microenvironments in modulating the angiogenic switch.

The process of metastasis is inextricably linked to angiogenesis. In primary tumors, an angiogenic switch is a necessary step to sustain its progressive expansion into a malignant form. Moreover, the neovasculature provides avenues for malignant cells to escape the primary site to establish metastatic lesions in secondary organs. These micrometastatic lesions usually remain dormant, and in some cases, they activate the angiogenic switch and progress into life threatening macrometastasis. Notably, the cellular and molecular mechanisms regulating the angiogenic switch and the dynamics of vessel assembly during this progression remain poorly understood, thereby limiting the utility of anti-angiogenic therapeutic approaches.
We use BM transplantation and murine models of human cancer to map the spatial and temporal windows of BM contribution as a function of cancer progression. By genetically marking the BM and tracking their lineages in vivo, we have identified the BM-derived endothelial progenitors as novel regulators of the angiogenic switch. Using spontaneous mouse models of breast cancer that metastasize to the lung, and BMT approached we have mapped the window of the angiogenic switch and have identified BM-derived endothelial progenitor cells as novel and critical regulators of the angiogenic switch. Indeed, this study has not only conceptually advanced our current knowledge of tumor metastasis, but has provided direct insights into the role of a specific component of the BM-derived microenvironment as an important regulator of the angiogenic switch. Several critical issues relating to the role of these cells are being investigated. For example, what is the origin of these progenitor cells, how general is their requirement in both pathogenic and physiological angiogenesis, and importantly what are the associated molecular mechanisms governing their mobilization, homing and proangiogenic functions. In addition, similar analysis is being extended to other components of the BM compartment.

2. Therapeutic targeting of the BM-derived microenvironment.

Our research also seeks to develop effective anti-angiogenic cancer therapies, and in this context we have demonstrated that ablation of endothelial progenitors impairs progression of primary tumors and metastatic lesions, and improves survival. These findings are paradigm shift and undoubtedly provide a foundation for very exciting clinical applications. Given that in many cancer patients, metastatic spread has already occurred by the time of primary diagnosis, this work suggests that selectively targeting the angiogenic switch via the endothelial progenitor cells may provide a clinically feasible approach to block metastasis progression and prevent death in cancer patients. For example, patients with advanced breast or colon cancers treated with chemotherapy following primary tumor resection frequently succumb to aggressive progression of metastatic lesions. Our studies suggest that combinations of adjuvant chemotherapy with anti-angiogenic agents to block recruitment of the endothelial progenitor cells may provide highly effective strategy to impair establishment of metastatic lesions. Given the clinical importance of these cells in metastasis development, we have developed effective collaborations with clinical experts to extend these insights into clinical translation that may lead to improved treatments in cancer patients.

3. Molecular mechanisms governing metastasis initiation and progression in the lung.

The progression of human cancer to the metastatic disease is the major contributing factor to its lethality. Notably, metastasis is one of the leading causes of death in cancer patients, with a high mortality due to the invasive nature of the disease and resistance to current treatment modalities. Despite the clinical importance, the cellular and molecular mechanisms that govern the initiation, establishment and progression of metastasis remain unclear. We are carrying out a systematic genome-wide analysis to identify patterns of gene-expression, microRNA/piRNA expression and epigenome changes that dictate how malignant primary tumors metastasize to the lung. The role of epithelial to mesenchymal transition (EMT), and acquisition of stem cell properties in this process is also an area of intense investigation in the laboratory. In addition, we are also actively examining the contribution of the microenvironment in sustaining both the initiation and progression of pulmonary metastatic lesions. From a clinical perspective, identification of metastatic-specific molecular determinants will not only have implications of being potential prognostic markers of metastasis, but the therapeutic targeting of these candidate molecules will have tremendous promise in prolonging the life of many cancer patients.

Genome-wide analysis using massively parallel sequencing technology and RNAi library screens in vivo.

We are continuing to develop technologies in the area of RNA interference and bioinformatic analysis of genomic data obtained through massively parallel sequencing and RNAi library screens.


Contact

Vivek Mittal, Ph.D
Principal Investigator
Department of Cardiothoracic Surgery
Department of Cell and Developmental Biology
Cornell University Medical Center
1300 York Avenue
525 East, 68th Street
Building A, Room 603C
New York, New York 10065

Office Phone - 212-746-9401
Lab Phone - 212-746-9400
FAX - 212-746-9393
E-mail - vim2010@med.cornell.edu