Function of NKG2D as a tumor growth factor receptor

Cancers adopt diverse strategies to safeguard their survival by evading tumor surveillance. The natural killer (NK) cell-activating receptor NKG2D, which is also expressed on effector T cells, plays a key role in host immune surveillance against cancer. Engagement of the immunoreceptor NKG2D by its ligand MHC class I chain-related protein A (MICA), which is frequently expressed on epithelial tumor cells but not on normal cells, promotes the human immune defense against cancer. In a surprising conceptual twist, the host laboratory of Dr. Thomas Spies at the Fred Hutchinson Cancer Research Center in Seattle, Washington, USA, observed that solid tumors including breast, ovarian, and prostate cancers paradoxically express NKG2D. Preliminary data suggest that above-threshold expression of NKG2D signaling complexes may activate the PI3K-AKT pathway and stimulate epithelial-to- mesenchymal transition (EMT) in tumor cells. The preliminary data support the idea that NKG2D complements the presence of MICA in a stimulatory loop that may promote tumor cell proliferation, growth, bioenergetic metabolism, and survival. In the here proposed studies, we will attempt to validate this model, which may advance knowledge of cancer development and malignancy and thus impact approaches to therapy. In the lab of Dr. Spies, we will investigate the previously unknown function of autocrine NKG2D stimulation as an important mediator in the activation of oncogenic signaling cascades. Using gain and loss of function approaches coupled to biochemical and functional studies, we will define the role of NKG2D signaling via the adaptor protein DAP-10 in the PI3K-AKT-mTOR and mitogen-activated protein (MAP) kinase pathways. Ensuing physiological effects of NKG2D-DAP10 signaling on proliferation and bioenergetic metabolism will be assessed, and its role in stimulating EMT analyzed. Finally, in the return phase at the Medical University of Vienna, I will continue our studies by applying breast, ovarian, and prostate cancer mouse models to define the biological effects of NKG2D- DAP10 signaling in tumor cells in vivo. The results from the planned studies may have substantial implications in advancing knowledge of cancer malignancy. As epithelial tumors frequently express the NKG2D ligand MICA among others, we should be able to substantiate the idea that acquisition of NKG2D by these cancers complements the presence of its ligands in an autocrine stimulatory loop. Taken together, we believe that the results may also have the potential to impact translational approaches to therapy as they relate to key areas including tumor growth factor signaling, progression, and malignancy.