Vanderbilt University School of Medicine

Gius, David R , MD, PhD

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Phone Number: 615-498-2829


Gius, David's picture

Office Address   Mailing Address

D4105 MCN

Department of Radiation Oncology 37232

Research Specialty
Radiation Oncology, Cancer Biology, Aging Genetics

Research Description
A fundamental observation in oncology is that the rate of malignancies increases significantly as a function of age, suggesting a potential mechanistic link between the cellular process governing longevity and the development of cancers. In fact, advanced age is the single most important predictive variable for cancer incidence; however, the genetics and murine models to investigate this idea have not been available. In this regard, the critical genes in longevity (or aging) have recently been characterized in S. cerevisiae and C. elegans, and the human homologs are referred to as the sirtuin gene family. It has been hypothesized that sirtuin genes may function as fidelity or repair genes and that loss or decrease of function, which normally occurs during aging, creates an environment permissive for age-related illness, including cancer. There are several common human solid tumor malignancies that have a very strong statistical connection to increased age, including B-cell lymphomas, multiple myeloma, and prostate and breast cancers.

Breast cancer has a very specific age-related incidence that increases until menopause and then increases more slowly until the mid 60s, when a second significant increase in incidence is observed. These breast malignancies, which develop over time, very likely represent a spectrum of cancers arising from genetic and epigenetic events that are observed in triple negative hereditary or spontaneous tumors observed in younger women. Murine models for hereditary breast cancer in younger women have been established by altering the expression of BRCA genes, and these mice develop triple negative (ER/PR negative, her2neu) tumors. In contrast, there are no or very few murine models for the spontaneous breast cancers that are more common in older women. Thus, it seems logical to assume that breast cancers that develop at a much later age are more likely to have a genetic or physiological connection to the cellular processes that govern mammalian aging.

To address this idea, over the past five years, we have constructed mice that have the three primary (SirT1-3) sirtuins genetically deleted. These mice, to varying degrees, develop several different types of malignancies; however, each also develops invasive ductal mammary tumors. These results seemed logical, since human sirtuins are the human homologs for the yeast and C. elegans longevity genes, and breast cancers have one of the strongest correlations to age. In addition, the sirtuin knockout mice do not develop mammary tumors until nearly one year, consistent with a murine model for spontaneous human breast cancer in women of an older age. Thus, it is proposed that the primary sirtuin family knockout mice may present a novel group of models to establish, validate, and investigate a subtype of human breast cancer.

The overarching goal my research is to use these novel sirtuin knockout mice as in vivo genetic models to connect aging genes, intracellular aberrant metabolism, and the mechanisms underlying the development breast cancer. The mice that lack SirT1 (Wang et al., 2009, Cancer Cell), SirT2 (submitted), and SirT3 (Kim et al., 2010, Cancer Cell) each develop breast cancer, and the levels of SIRT1-3 are also decreased in human breast cancer samples, as compared to normal breast tissues. SIRT2 and SIRT3 are the primary cytoplasmic and mitochondrial deacetylates0 and mice MEFs lacking SirT2 and SirT3 exhibit altered intracellular and mitochondrial metabolism as well as develop well differentiated, ER/PR ductal mammary tumors. Thus, we propose that these murine models can subsequently be used to determine the mechanisms for breast cancer development as well as the identification genetic factors in disease progression. These models would also be used for drug discovery that is actively being investigated as part of the Vanderbilt SPORE, to validate potential new agents for chemoprevention and/or therapy.

Clinical Research Description
As a clinician in the Department of Radiation Oncology I spend roughly 30% of my time consisting of patient care as well as the development, design, and the subsequent approval of clinical studies in the Section. In this regard, I am chief of the Radiation Thoracic Oncology service where I collaborate with the chiefs of the thoracic services of Medical Oncology and Thoracic Surgical Oncology in the management of the Thoracic Multi-Modality Oncology Program. I am also a member of the Vanderbilt Lung SPORE where I provide both input into the clinical and research aspects of this collaborative research program. I am also responsible for the generation of clinical research and protocols in participation with the other members of Radiation Oncology and the Thoracic Oncology Program In addition, I work with these team members to integrate this clinical activates with my basic and translation science that center on model systems using in vitro and in vivo tumors and tumor cell lines to investigate the mechanisms of carcinogenesis and tumor cell resistance.

Clinical Interests
Lung and CNS malignancies

Kim H-S, Vassilopoulos A, Wang R-H, Lahusen T, Xu Z, Xiao Z, Xu Z, Li C, Veenstra T.D, Li B, Yu H, Ji J, Wang X.Y, Park S-H, Cha Y, Gius D, and Deng C-X. Mitotic dysfunction leads to genetic instability and tumorigenesis in mice lacking Sirt2. Cancer Cell, 20, 1-13, 2011.

Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, Verdin E. . Dietary restriction: standing up for sirtuins. Science, 329, 1012-1013, 2010.

Kim, HS, Patel, K, Muldoon-Jacobs, K, Bisht, KS, Aykin-Burns, N, Pennington, JD, van der Meer, R, Nguyen, P, Savage, J, Owens, KM, Vassilopoulos, A, Ozden, O, Park, SH, Singh, KK, Abdulkadir, SA, Spitz, DR, Deng, CX, Gius, D. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell, 17(1), 41-52, 2010.

Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Molecular Cell, 40(6), 893-904, 2010.

Yu, W, Gius, D, Onyango, P, Muldoon-Jacobs, K, Karp, J, Feinberg, AP, Cui, H. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature, 451(7175), 202-6, 2008. PMCID:2743558

Gius, D, Cui, H, Bradbury, CM, Cook, J, Smart, DK, Zhao, S, Young, L, Brandenburg, SA, Hu, Y, Bisht, KS, Ho, AS, Mattson, D, Sun, L, Munson, PJ, Chuang, EY, Mitchell, JB, Feinberg, AP. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell, 6(4), 361-71, 2004. PMCID:2743558

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