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Lisa Coussens
The overall goal of our research program is to define cellular, molecular and microenvironmental determinants of cancer development. My research is based upon the premise that, in addition to intrinsic changes occurring within neoplastic cells, e.g., activation of oncogenes and inactivation of tumor suppressor genes, extrinsic factors, e.g., inflammation, extracellular matrix (ECM) remodeling and angiogenesis also regulate critical properties of tumor evolution.
During the early development of cancer, many physiological processes occur in the vicinity of 'young tumor cells' that are similar to processes that occur during embryonic development and to healing of wounds in adult tissue, e.g., leukocyte infiltration, activation of pre-existing vasculature and development of new blood supply (angiogenesis) and extensive tissue remodeling. During wound healing, immune cells are recruited to sites of injury to eliminate potential bacterial infection as well as to facilitate healing by providing growth factors and proteases that are essential to the process. In so doing, tissue remodeling occurs and accommodates generation of a new blood supply that further helps the tissue heal. When 'healing' is complete, inflammation and tissue remodeling resolves and the tissue returns to its former state. Several of these parameters are conserved during tumor development; however, instead of initiating a 'healing' response, inflammatory cells, tissue remodeling and angiogenesis provide growth-promoting factors that promote tumor development. By studying mouse models of skin and breast cancer development, the Coussens lab is identifying important cellular pathways and molecules involved in regulating tumor-associated inflammation, tissue remodeling and angiogenesis. Identification of these important regulatory mechanisms will reveal drug-targets that can then be used to design novel therapeutic strategies for treating and imaging cancer development in humans.
Other Research in Dr. Coussen's lab
Inflammation
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Larry Fong
Our program is focused upon defining the immune response to tumor antigens in order to develop potential vaccine and immunotherapeutic strategies. Currently, our research program is divided into three distinct but interrelated areas of interest. These include studying dendritic cell biology, exploring approaches to break tolerance against self-antigens, and characterizing effector and memory T cells following tumor immunotherapy.
Dendritic cell function
Dendritic cells (DC) are known to be comprised of multiple subsets (e.g. myeloid DC, plasmacytoid DC), each of which may have distinct functions. By studying different DC subsets in the context of malignancy, we hope to develop approaches to use DC as a means of inducing therapeutic antitumor immunity in vivo in both animal models and cancer patients.
Tolerance to tumor associated antigens
The majority of the current tumor-associated antigens represent self-antigens that are either aberrantly or overly expressed by the malignancy. As a result, the vast majority of solid tumors are not immunogenic. We are using mouse and human models to define the antigen specificity of anti-tumor immune responses that either occur spontaneously or are induced with immunotherapy.
Evaluating antigen-specific T cell responses.
We have demonstrated that in vivo expansion of CD8 T cells identified with MHC/peptide tetramers can correlate with tumor responses in cancer patients. Current efforts underway are to characterize the T cell response following vaccination against tumor associated (self) antigens utilizing novel assays that couple tetramer staining (antigen-specificity) with T cell function. Moreover, we are currently characterizing the immune response not only within the blood, but also within the tissues and tumors in order to examine the distribution of an immune response. By identifying the dynamics of antigen specific T cells and their capacity to develop immunologic memory, we hope to develop improved strategies in tumor immunotherapy.
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Matthew Krummel
The lab is currently using advanced imaging to visualize T cell activation in tumor draining lymph nodes and effector sites. We are generating two models—one for breast cancer and one for melanoma—in which the tumors are fluorescent. Interactions between tumors and T lymphocytes are revealed uing fluorescent dyes, including GFP fusions.
Other Research in Dr. Krummel's lab
Autoimmunity • Immune Regulation • Immune Receptors and Signaling
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Lewis Lanier
NK cells have the ability to recognize and kill transformed cells without prior immunization (Lanier, Nat. Med. 2001 Nov. 7(11):1178-80). The NKG2D receptor expressed on NK cells and CD8+ T cells recognizes a family of MHC class I-related proteins, which includes in humans the MICA, MICB, and ULBP proteins and in mice the RAE-1, H60 and MUTL1 proteins. (Cerwenka et al. Immunity. 2000 Jun;12(6):721-7). These NKG2D ligands are generally not expressed on normal, health tissues in adults; however, they are frequently over-expressed by many types of tumors. Expression of NKG2D ligands on tumors can initiate NK cell activation and result in tumor rejection (Cerwenka et al. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11521-6 ). Current studies in our lab focus on the NKG2D ligands, as well as other NK receptors that have been implicated in anti-tumor immunity.
Other Research in Dr. Lanier's Lab
HIV and Viral Immunity • Diabetes and Autoimmunity • Immune Receptors and Signaling
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Steve Rosen
The Rosen lab is interested in the role of two extracellular sulfatases (Sulf1 and Sulf2) in cancer. These enzymes modify heparan sulfate proteoglycans and potentiate wnt signaling. These enzymes are upregulated in a number of cancers (including multiple myeloma) and appear to promote cell proliferation and survival in some tumors.
Other Research in Dr. Rosen's lab:
Development and Differentiation • Immune Receptors and Signaling • Inflammation
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Bill Seaman
Our laboratory is interested in the receptors that activate or inactivate natural killer (NK) cells, which spontaneously kill tumors.
Other Research in Dr.Seaman's Lab
Allergy and Asthma • Immune Receptors and Signaling • Immune Response to Microbial Pathogenesis
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Matthias Wabl
Tumor suppressors in lymphocytes
The genes that are necessary for normal, controlled cell growth are called tumor suppressor genes, and inactivation of these genes can lead to tumor formation. The majority of known tumor suppressors were located by the genetic mapping of organisms with an inherited predisposition for cancer. However, familial predisposition to cancer is responsible for only approximately 10% of human cancers and identification of tumor suppressors involved in non-familial cancers has been slower. The goal in the lab is to define the set of tumor suppressors that when deleted contribute to the formation of lymphocyte tumors in mice; and their interactions with protooncogenes, as completely as possible.
We define cancer genes by retroviral insertional mutagenesis, combined with chemical mutagenesis, to inactivate both alleles in cells of a given mouse. The offspring of chemically mutagenized male mice are subjected to insertional mutagenesis by retrovirus that induces tumors of lymphocyte origin. The viral genome disrupts potential suppressor genes, leading to their inactivation, and at the same time creates a marker for identifying the insertion loci. The tagged cancer genes are cloned and sequenced. In collaboration with several other labs, we characterize a subset of the cancer genes and determine the nature of their cooperation with other oncogenes (co-mutations).
Other Research in Dr. Wabl's lab:
Development and Differentiation • Immune Receptors and Signaling • Inflammation
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Zena Werb
The host response to tumorigenesis includes the recruitment of innate and acquired immune cells. We are using transgenic mice and intravital microscopy to investigate the mechanisms by which inflammatory and immune cells enhance mammary tumor development by regulating angiogenesis, tumor growth and tumor dissemination.
Other Research in Dr. Werb's lab:
Immune Response to Microbial Pathogens • Inflammation • Development and Differentiation
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