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Welford Lab

Hypoxia, radiobiology, and tumor microenviroment

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Investigator / Contact Person Scott Welford

Research

Lipid deposition and signaling in renal cancer:  Hypoxia is a major driver of several of the “Hallmarks of Cancer” identified by Hanahan and Weinberg, mostly through hypoxia inducible factor (HIF) driven gene expression.  We have been interested in the VHL-defective renal cancer model because it displays constitutive HIF target gene expression, and remains a disease with very poor prognosis.  Our studies have focused in several hypoxia dependent processes, including monocyte infiltration, angiogenesis, and most recently lipid deposition and metabolism.  We are particularly interested in tumor-derived secreted factors that mediate essential phenotypes and can easily be both detected and therapeutically targeted, and can therefore have significant translational impact.


Mechanisms of radiation resistance: The tumor microenvironment has a well-recognized impact on the response of cells to ionizing radiation (IR). Hypoxia, through both altered gene expression and deprivation of molecular oxygen, affects the response of cells to the oxidative stress of IR. We sought to gain a foothold on the longstanding question of why cells of some tumor types display a heightened survival (resistance) when exposed to ionizing radiation compared to cells of the corresponding normal tissue. We employed a state-of-the-art knockdown library technique to determine genes expressed in brain tumors that promote resistance to IR. In silico analyses of the results of the screen allowed us to focus on genes with elevated expression in brain tumors compared to normal brain, as well as genes whose expression correlated with poorer outcome of patients with brain tumors. Among the list of "hits," we identified the polyamine regulatory enzyme SAT1 as elevated in brain tumors, correlating with poor patient outcome, and mechanistically involved in homologous recombination. We discovered that SAT1 promotes BRCA1 gene expression by driving histone acetylation. Thus, cancer cells with elevated SAT1 are more prepared to respond to IR. We further found that SAT1 is regulated at the level of transcription by redox stress, including hypoxia/reoxygenation. Therefore, our findings identify SAT1 as a therapeutic target in brain tumors that is regulated by the microenvironment to promote radiation resistance. 


Effects of cosmic radiation on cognitive defects and carcinogenesis:  One of the major health concerns on long-duration space missions will be radiation exposure to the astronauts. Outside the earth's magnetosphere, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events (SPE) that are composed principally of protons and nuclei of He, O, Ne, Si, Ca, and Fe.  Protons are by far the most common species, but the higher atomic number particles are thought to be more damaging to biological systems. Evaluation and amelioration of risks from GCR exposure will be important for deep space travel.  Two of the major gaps in knowledge exist in quantification of risk of cognitive defects and of cancer development.  My group has engaged in studies of cognition and of hematopoietic malignancy in animal models concurrently to reduce risk uncertainty in these two areas. The hematopoietic system is one of the most radiation-sensitive organ systems, and is highly dependent on functional DNA repair pathways for survival.  Recent results from our collaborators have demonstrated an acquired deficiency in mismatch repair (MMR) in human hematopoietic stem cells (HSCs) with age due to functional loss of the Mlh1 protein, suggesting an additional risk to astronauts who may have significant numbers of MMR deficient HSCs at the time of space travel.  Thus our efforts have focused on assessing development of hematopoietic malignancy after simulated cosmic radiation in MMR deficient animals, in which we have found dramatic sensitization to cancer incidence.