Massey researcher receives NIH grant to study unknown factors controlling adaptive low-oxygen cell response that aids in cancer growth
Massey researcher Keith Baker, Ph.D., received a $219,030 Exploratory/Developmental Research (R21) grant from the National Institutes of Health to identify the components that help cells adapt and survive in low-oxygen conditions that occur in novel cell signaling pathways. Low-oxygen responses typically occur in the Hypoxia-Inducible Factor (HIF) pathway, but Baker will be looking at the responses that occur in independent signaling pathways. This study will be the first of its kind that will specifically assess HIF-independent low-oxygen responses in an intact organism.
All higher organisms express Hypoxia-Inducible Factor-1, a type of gene that regulates the body’s response to low oxygen. One typical response is angiogenesis, a process that involves the creation of new blood cells to feed new tissue. This adaptive response, like others, can be helpful or harmful depending on the body’s ability or inability to regulate the expression of the genes necessary for survival in low oxygen. For instance, angiogenesis is a necessary response to hypoxia (low oxygen) for the proper development of the human embryo, but conversely can allow cancerous cells to grow and multiply as new blood vessels feed new and growing tissue. Because hypoxia tolerance and signaling are two major factors that drive tumor growth, the ability to target particular adverse responses is crucial—cancer cells will starve and die in hypoxic conditions if there is no response to help them adapt.
HIF-dependent responses are not the only responses that exist. In previous studies,* Baker, who is a member of Cancer Cell Signaling research program at Massey and assistant professor of biochemistry and molecular biology at the VCU School of Medicine, established that response and adaptation to hypoxic conditions can also take place in signaling pathways that operate independently of the HIF pathway. The study determined the existence of additional unidentified genes necessary for low-oxygen responses in novel pathways.
“The R21 grant will allow us to identify the unknown factors that we know exist and work in HIF-independent response programs,” Baker says. “We can then determine ways in which these genes can be activated when not functioning properly and also devise ways to target them when they are causing harm, such as in cancerous tumor growth.”
Baker will experiment with HIF-independent responses in flies, leaving the HIF pathway untouched. He hopes to discover the components behind the unique adaptive responses using randomly mutated transgenic flies that will glow when one of the unknown factors controlling the response to low oxygen is affected. Flies are the preferred organism for genetic screening—practical and financial reasons aside, results are from living, intact organisms versus those from cell culture systems where comparable genetic testing with mice and other animals takes place. Studying the physiologic response is an important step in moving forward with the screening results. Once observed in the fly, the genetic findings will be translated into other mammalian systems, a type of approach that has been the basis for major genetic findings in the past. The study’s long-term goal is to identify new, important genes necessary for low-oxygen responses so that targeted treatments can be developed in order to disrupt cancer cell growth.
*Li, Y., D. Padmanabha, L. B. Gentile, C. I. Dumur, R. B. Beckstead, and K.D. Baker. (2013). HIF- and non-HIF-regulated hypoxic responses require the estrogen-related receptor in Drosophila melanogaster. PLoS Genet 9: e1003230; Padmanabha, D., P. A., Padilla, Y. J. You, and K. D. Baker. (2015). A HIF-Independent Mediator of Transcriptional Responses to Oxygen Deprivation in Caenorhabditis elegans. Genetics 199: 739-748.