Research Departments & Organizations
Therapeutic Radiology: Radiobiology
My lab focuses on two main areas of research with a goal to provide pertinent insights for the mechanistic understanding of human diseases. First, we are trying to understand the mechanisms by which stem cell maintenance and differentiation are regulated by environmental factors such as oxygen or by epigenetic mechanisms involving microRNAs. We are particularly interested in regulation of cancer stem cell functions. The second area of our research concerns the role of oxygen-sensing pathway in the regulation of energy homeostasis, in the pathological progression of obesity, and in obesity-associated metabolic syndromes including type 2 diabetes and cardiovascular diseases. More details can be found in the Yun Lab web page (https://medicine.yale.edu/lab/yun/) or by click the link on the left.
Specialized Terms: Molecular and cancer biology; Stem cell biology; hypoxia; microRNA; tumor microenvironment; Obesity and metabolic syndromes
Extensive Research Description
Oxygen is essential to all aerobic life forms on earth. In addition to its role in energy metabolism, oxygen has broad biological impact from embryogenesis to adulthood. This notion is strongly supported by the fact that mammalian embryos develop in a low oxygen or hypoxic environment (approximately 3% O2 or less) during the first trimester. Furthermore, recent studies from us and other laboratories have shown that oxygen can directly regulate the differentiation of stem/precursor cells, and may participate in the maintenance of stem cells in the stem cell niche.
Our overall research interest is to investigate the mechanisms by which tissue microenvironment, especially hypoxia, regulates the important biological processes including cellular differentiation, metabolism, tumor progression and tumor response to therapy. Our current focuses are (1) the role of hypoxia in the regulation of stem cell maintenance and differentiation, (2) the effects of hypoxia on cancer cell differentiation, malignant progression and response to therapy, (3) the role of HIF pathway in adipocytes and myocytes, especially in the regulation of energy homeostasis, and the pathogenesis of obesity and/or type 2 diabetes.
The oxygen-sensing pathway and regulation of cancer stem cell functions.
Nearly all of solid tumors contain areas of hypoxia. Tumor hypoxia is strongly correlated with advanced disease stage and poor clinical outcome. Increasing amounts of evidence suggest that hypoxic tumor cells tend to be poorly differentiated. We hypothesize that hypoxia inhibits cancer cell differentiation and thus arrests tumor cells in their undifferentiated state, which represents a novel approach to the understanding of tumor progression under hypoxic conditions. Poorly differentiated tumor cells are almost always more tumorigenic and more malignant than their more differentiated counterparts. The extensive proliferative potentials and long lifespan will allow the undifferentiated tumor cells to accumulate stable genetic and epigenetic changes that eventually confer the malignant phenotype. Therefore, hypoxia-mediated differentiation arrest of tumorigenic cells provides a platform that allows continuous accumulation and perpetuation of both genetic and epigenetic changes that result in tumor malignancy. Currently, we are using several tumor model systems to test this hypothesis. These studies will have the potentials to provide new approaches toward effective therapy for solid tumors, e.g. by specifically targeting the undifferentiated cancer stem cell population in the hypoxic regions.
The oxygen-sensing pathway and metabolism: Implications in obesity and diabetes.
Obesity has become a world wide epidemic and is associated with more than 30 human diseases including type 2 diabetes, cardiovascular disease, and cancer. Adipose tissue plays a critical role in the development of obesity and other metabolic syndromes. It has been shown that obesity results in adipose tissue hypoxia, suggesting that the oxygen-sensing pathway would play a key role in the pathological progression of obesity and its related diseases.
We were the first to investigate the mechanisms by which HIF-1 regulates the adipogenic differentiation. We have found that HIF-1 is both necessary and sufficient to inhibit the adipogenic differentiation of preadipocytes. Furthermore, hypoxia arrests preadipocytes in their stem/precursor state. We have generated a genetic mouse model to test the hypothesis that HIF plays an important role in the development and functions of adipose tissue, as well as in the pathogenesis of obesity and related metabolic syndromes including diabetes and cardiovascular diseases.
The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells.
Kim H, Lin Q, Glazer PM, Yun Z. The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Research : BCR 2018, 20:16. 2018
The anti-protozoan drug nifurtimox preferentially inhibits clonogenic tumor cells under hypoxic conditions.
Li Q, Lin Q, Kim H, Yun Z. The anti-protozoan drug nifurtimox preferentially inhibits clonogenic tumor cells under hypoxic conditions. American Journal Of Cancer Research 2017, 7:1084-1095. 2017
Cellular and molecular mechanisms underlying oxygen-dependent radiosensitivity.
Liu C, Lin Q, Yun Z. Cellular and molecular mechanisms underlying oxygen-dependent radiosensitivity. Radiation Research 2015, 183:487-96. 2015
Hypoxia and regulation of cancer cell stemness.
Yun Z, Lin Q. Hypoxia and regulation of cancer cell stemness. Advances In Experimental Medicine And Biology 2014, 772:41-53. 2014
Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy.
Lin Q, Huang Y, Booth CJ, Haase VH, Johnson RS, Celeste Simon M, Giordano FJ, Yun Z. Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy. Journal Of The American Heart Association 2013, 2:e000548. 2013
Interaction of delta-like 1 homolog (Drosophila) with prohibitins and its impact on tumor cell clonogenicity.
Begum A, Lin Q, Yu C, Kim Y, Yun Z. Interaction of delta-like 1 homolog (Drosophila) with prohibitins and its impact on tumor cell clonogenicity. Molecular Cancer Research : MCR 2014, 12:155-64. 2014
Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha.
Lin Q, Cong X, Yun Z. Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha. Molecular Cancer Research : MCR 2011, 9:757-65. 2011