Fbxo2: a master regulator of lung cancer metastasis?
Initial Award Abstract
Fbxo2 in ECM and Integrin Control and Lung Tumor Metastasis Nearly 14,000 men and women in California will die of lung cancer this year. The vast majority of these deaths will be caused by complications arising from a primary lung cancer metastasizing to distant sites or organs in the patient’s body. If metastasis could be prevented or attenuated, lung cancer would be far more manageable with chemotherapy and mortality rates for the disease would undoubtedly decline. Metastasis is a complex process involving cellular aspects such cell-cell communication, motility, adhesion, invasion, and angiogenesis. This high level of complexity makes metastatic lung cancer extremely difficult to treat in the clinic. Two very important players in lung cancer metastasis are the extracellular matrix (ECM) and integrins. The ECM provides a layer of support for lung epithelial and stem cells, formed of a matrix of fibrous proteins such as laminins, collagens, and fibronectin. Integrins are proteins expressed on the surface of lung cells that form contacts with ECM and surrounding cells. Integrins also transmit environmental information and growth signals to lung cells. Importantly, ECM and integrin proteins are known to undergo severe alterations during the progression of lung cancers to metastasis. These changes are essential for a lung tumor cell or cancer stem cell to migrate away from the primary tumor, invade the vasculature, and form a metastatic tumor elsewhere in the body. However, the molecular mechanism responsible for these alterations in lung cancers is not understood. We have identified a protein called Fbxo2 that regulates the level of many ECM and integrin proteins in lung cancer cells. Fbxo2 was previously shown to play a role in a process that regulates protein quality within lung epithelial cells. We have found that when Fbxo2 is repressed in lung tumor cells, the levels of many ECM and integrin proteins are dramatically increased. Included in this group of proteins are integrin beta1, integrin alphaV, and laminin 5, and others, that are known to play important roles in lung tumor metastasis. Furthermore, Fbxo2 expression is repressed in lung tumors compared to normal lung epithelium. Our hypothesis is that Fbxo2 is a “master regulator” of ECM and integrin proteins in lung cancer cells. Repression of Fbxo2 function leads to alterations in ECM and integrin proteins that promote the metastatic progression of lung cancers. This research project is the first to explore the existence of a “master regulator” for ECM and integrin proteins in lung cancer cells. It is also the first to suggest that the protein quality control system could play a significant role in lung tumor metastasis. This research proposal studies the pathogenesis of lung cancer disease progression, directly addressing the “Lung Cancer” research priority of the TRDRP. Understanding the role that Fbxo2 plays in ECM and integrin control in lung cancer cells will likely identify novel molecular targets for the rational design of drugs that prevent the metastatic progression of lung cancers. These drugs would provide hope to those afflicted with metastatic life-threatening disease, improve their quality of life, and help to lower the mortality associated with the disease. |