The central theme of the Cancer Cell Biology Program (formerly the Cell Signaling and Growth Control Program) is to define the complex mechanisms whereby selected signal transduction pathways regulate cell proliferation, survival, invasive activity and the immune responses that occur in tumor development and metastasis.

Peer-reviewed	$13.3M	41
NCI	$3.7M	13
NIH	$8.3M	20
ACS	$0.1M	1
NSF	$ 0M	0
Other P-R	$1.2M	7
Non peer-reviewed	$1.2M	7
Total	$19.3M	82

• To delineate the mechanisms governing cell adhesion, motility and invasion with an emphasis on defining the contribution to tumor biology of 1) the function/signaling of the integrins and other cell adhesion molecules and 2) the assembly, turnover and structure of the extracellular matrix.
• To define the mode of action of several classes of growth factor receptors, cell adhesion molecules and other hormones with respect to the control of tumor cell cycle progression, proliferation and survival.
• To examine the role of discrete signaling pathways, DNA damaging events, mRNA stability and epigenetic factors in the regulation of gene transcription and protein translation as they relate to cancer cell biology.
• To establish methods for the study of stem cells, with an emphasis on evaluating the potential role of stem cells as tumor precursors and assessing their growth dynamic as a determinant of tumor susceptibility.
• To elucidate the cellular mechanisms associated with activation of the innate immune system and how these processes contribute to the in vivo recognition and destruction of tumor cells, including a dissection of the mechanisms of T cell suppression and the disruption of immune memory seen in cancer.
• To identify novel therapeutic strategies that target tumor-associated signaling mechanisms and are relevant to the etiology and treatment of cancer.
• To collaborate with UWCCC programs to translate basic science into clinical evaluation and application.

Significant Discoveries

• Demonstration of a role of PI kinases in the ability of cells to form focal contacts, adhere to the extracellular matrix, change morphology, and migrate, all of which are essential for cancer cell metastasis. (Nature 420: 89-93, 2002)
• Introduction of a new paradigm of NF-κB regulation by demonstrating that a series of post-translational modification events initiated by DNA damaging agents mediates a novel nuclear to cytoplasmic NF-?B activation pathway to induce cancer cell resistance. (Cell 115:565-576, 2003)
• Inhibition of IκBα nuclear export as an approach to abrogate Nuclear Factor B-dependent Cancer Cell Survival. (Molecular Cancer Research 3:42-49, 2005)
• Molecular linkage between the kinase ATM and NF-?B signaling in response to genotoxic stimuli. (Science 311:1141-1146, 2006)
• Implication of a family of intracellular, limited proteases, the calpains, as a key molecular control point in attachment of cells to the surrounding matrix. (Nature Cell Biology 6:977-987, 2004)
• Demonstration that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands in vivo. (Proc Natl Acad Sci USA 10:4158-63, 2004)
• Characterization of the role of a novel E3 ubiquitin ligase (GRAIL) in T cell anergy and movement towards incorporation into clinical applicability and clinical monitoring. (Nature Immunol 5:45-54, 2004)
• Contribution of CD1d-restricted T cells to antitumor effects and the maintainence of peripheral tolerance. (Nature Immunol 4:517-23, 2003)
• R-Ras control of membrane protrusion and migration of human breast cancer cell through the spatial regulation of Rac and Rho. (Molecular Biology of the Cell 16:84-96, 2005)
• Use of liquid crystals to report the level and activity of membrane proteins of interest to cancer development and therapeutics, such as EGF receptor and Ras, that have been captured by affinity microcontact printing from tumor cell lysates and membrane extracts. (Journal of the American Chemical Society 127:8912-8913, 2005)
• Expansion of human γδ T cells by non-peptidic phospho-antigens and application of this concept to clinical trials in 3 diseases (prostate cancer, renal cell cancer, and neuroblastoma). (Immunology Lett 96:3-9, 2005)