The major scientific focus of this program is to provide improved understanding of the signaling pathways that contribute to cancer. For example, the important connection between inflammation and cancer; the key role of the tumor microenvironment in progression; the roles of receptor tyrosine kinases, nuclear receptors, transcription factors and chromatin remodeling proteins in specific malignancies (breast cancer, prostate cancer, colorectal cancer, lung cancer, melanoma and glioma); and the multiple roles of the TGFβ in tumorigenesis.
The Cancer Cell Signaling Program is organized around 4 focus areas:
Cytokine Signaling, Inflammation, and Cancer
Leaders: Xiaoxia Li, PhD
The Cytokine Signaling, Inflammation, and Cancer focus group includes investigators with interests in innate immune signaling pathways that lead to inflammatory responses and cancer. Included are studies of cytokines (TGFβ, interferons), Toll-like receptors (TLRs), and key stress-inducible transcription factors (STATs, NFκB).
Nuclear Receptor Signaling and Hormone Responsive Cancers
Leaders: David Danielpour, PhD and Noa Noy, PhD
The Nuclear Receptors focus group includes investigators with interest in nuclear hormone receptors, ligand-activated transcription factors that regulate gene expression in response to small hydrophobic hormones, such as steroid hormones, vitamin D, thyroid hormone, and metabolites of vitamin A, long chain fatty acids, and cholesterol. Nuclear receptors and their ligands control key aspects of cellular metabolism, differentiation, proliferation, and apoptosis, and they play key roles in multiple biological functions during embryonic development and in the adult. The group aims to obtain new insights into molecular mechanisms that underlie the transcriptional activities of nuclear receptors, that govern their cross-talk with other signaling pathways, that integrate into biological functions at the cellular and organismal levels, and that are ultimately involved in human health and disease. Of special interest is the utilization of information derived from these investigations for developing strategies that will target receptors and their associated coregulators for prevention of and therapeutic interventions in cancer.
Leader: William Schiemann, PhD
The TGFβ focus group brings together a group of basic scientists and physician-scientists with a common interest in exploring the basic biology and biochemistry of TGFβ signaling, and a shared goal to define the complex roles of this pathway in disease pathogenesis and carcinogenesis. During the earliest stages of carcinogenesis TGFβ principally functions as a tumor suppressor. However, during the later stages of malignant progression biologically active TGFβ, often produced by cancer cells, can aid tumor growth and metastasis through the ability to suppress immune cells, enhance angiogenesis, promote matrix production and induce cancer cell migration. By this time, most tumors have become refractory to the growth inhibitory effects of the cytokine, often through mechanisms involving the downregulation of expression of TGFβ receptors at the cell surface.
Tumor Microenvironment and Metastasis
Leaders: Danny Manor, PhD
Members of this focus group investigate the role of cell surface and extracellular cues as well as their signaling pathways in tumorigenesis. This focus group will facilitate interactions among the Cancer Center Members that research similar biological processes in different types of cancer.
Tumor cells are influenced by their extracellular environment which can facilitate uncontrolled growth, invasion and metastasis. The cues that regulate tumor cells include growth factors, cell adhesion molecules and extracellular matrix proteins. In most tumor cells, growth factor signaling is constitutively active indicating its importance to tumorigenesis. These types of molecules may be produced by the tumor cells themselves or synthesized by the surrounding stromal cells in their local environment.
These extracellular or cell surface cues converge on various signaling pathways to regulate cell adhesion, growth and migration. The ability of tumor cells not only to recognize these cues but to alter their surrounding environment is key to both migration and invasion which are prerequisites for metastasis. Improved clinical treatment and the creation of novel therapeutics require that we understand the basic signaling pathways that regulate metastatic progression.
Edward M. Greenfield, PhD