1. Neuroendocrine modulation of energy balance and its effects on cancer. Our laboratory demonstrates that environments that are more complex and challenging, but not stressful per se, exert beneficial effects on body composition, energy balance, and peripheral cancer progression. We are the first to demonstrate that environmental enrichment, a favorable environment boosting mental health, inhibits cancer progression and has discovered a specific neuroendocrine axis—the hypothalamic-sympathoneural-adipocyte (HSA) axis as one key mechanism, with BDNF as the upstream mediator in the brain and leptin as the downstream mediator in the periphery. Furthermore, we have revealed a novel avenue to induce brown-like adipocyte in the white fat that is also mediated by the HSA axis. The environmental or genetic activation of the HSA axis leads to resistance to diet-induced obesity and reversal of genetic forms of obesity. Our research on the HSA axis provides novel targets for the prevention and treatment for cancer, obesity, and related metabolic syndromes. We have expanded this work to multiple solid tumor models as well as leukemia models, and continue to identify additional mediators along the HSA axis.
a. Cao, L*, Liu, X, Lin, EJ, Wang, C, Choi, EY, Riban, V, Lin, B, During, MJ. Environmental and genetic activation of a brain-adipocyte BDNF/Leptin axis causes cancer remission and inhibition. Cell 2010, 142, 52-64. PubMed PMID: 20603014; PubMed Central PMCID: PMC3784009. (* corresponding author)
b. Cao, L*, Choi, EY, Liu, X, Martin, A, Wang, C, Xu, X, During, MJ. White to brown fat phenotypic switch induced by genetic and environmental activation of hypothalamic-adipocyte axis. Cell Metabolism 2011, 14, 324-338. PubMed PMID: 21907139; PubMed Central PMCID: PMC3172615. (* corresponding author)
c. Liu, X, McMurphy, T, Xiao, R, Slater, A, Huang, W, Cao, L. Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice. Mol Ther 2014, 22, 1275-1284. PubMed PMID: 24637454; PubMed Central PMCID: PMC4089014.
d. During, M, Liu, X, Huang, W, Magee, D, Slater, A, McMurphy, T, Wang, C, Cao, L. Adipose VEGF links the white-to-brown fat switch with environmental, genetic, and pharmacological stimuli in male mice. Endocrinology 2015, 156, 2059-2073. PubMed PMID: 25763639; PubMed Central PMCID: PMC4430610
2. Neural-immune interactions. In collaboration with Caligiuri lab, we reveal how environmental enrichment via hypothalamic BDNF regulates thymus, secondary lymphoid tissues, as well as adipose resident immune populations in health and diseases including autoimmune diseases, obesity, and cancer.
a. Xiao, R, Bergin, SM, Huang, W, Slater, AM, Liu, X, Judd, RT, Lin, EJ, Widstrom, KJ, Scoville, SD, Yu, J, Caligiuri, MA, Cao, L. Environmental and genetic activation of hypothalamic BDNF modulates T-cell immunity to exert an anticancer phenotype. Cancer Immunol Res 2016, 4, 488-497. PubMed PMID: 27045020 PubMed Central PMCID: PMC4891265 DOI: 10.1158/2326-6066.CIR-15-0297.
b. Xiao, R, Bergin, SM, Huang, W, Mansour, AG, Liu, X, Judd, RT, Widstrom, KJ, Queen, NJ, Wilkins, RK, Ali, S, Caligiuri, MA, Cao, L. Enriched environment regulates thymocyte development and alleviates experimental autoimmune encephalomyelitis in mice. Brain Behav Immun 2019, 75, 137-148. PubMed PMID: 30287389 DOI: 10.1016/j.bbi.2018.09.028.
c. Mansour, AG, Xiao, R, Bergin, SM, Huang, W, Chrislip, LA, Zhang, J, Ali, S, Queen, NJ, Caligiuri, MA, Cao, L. Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice. Eur J Immunol 2021, 51, 557-566. PubMed PMID: 33169371 DOI: 10.1002/eji.201948358.
d. Bergin, SM, Xiao, R, Huang, W, Judd, CRT, Liu, X, Mansour, AG, Queen, NJ, Widstrom, KJ, Caligiuri, MA, Cao, L. Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells. Brain Behav Immun 2021, 95, 447-488. PubMed PMID: 33989745 DOI: 10.1016/j.bbi.2021.05.005.
3. Environmental and lifestyle factors affecting aging. We demonstrate that environmental enrichment promotes healthy aging likely mediated by hypothalamic BDNF. Currently we are investigating the role of hypothalamic microglia in the environmental enrichment-induced metabolic adaptions in aged mice, and whether hypothalamic BDNF plays a role in enrichment-induced microglia modulation.
a. McMurphy, T, Huang, W, Queen, NJ, Ali S, Widstrom, KJ, Liu, X, Xiao R, Siu JJ, Cao L. Implementation of environmental enrichment after middle age promotes healthy aging. Aging (Albany NY) 2018 10:1698-1721. PubMed PMID: 30036185 DOI: 10.18632/aging.101502.
b. McMurphy, T, Huang, W, Liu, X, Siu, JJ, Queen, NJ, Xiao, R, Cao, L. Hypothalamic gene transfer of BDNF promotes healthy aging in mice. Aging Cell 2019: e12846. PubMed PMID: 30585393; DOI: 10.111/acel.12846
c. Ali, S, Liu, X, Queen, NJ, Patel, RS, Wilkins, RK, Mo, X, Cao, L. Long-term environmental enrichment affects microglial morphology in middle-aged mice. Aging (Albany NY) 2019 11:2388-2402. PubMed PMID: 31039130 DOI: 10.18632/aging.101923.
d. Ali, S, Mansour, AG, Huang, W, Queen, NJ, Mo, X, Anderson, JM, Hassan II, QN, Patel, RS, Wilkins, RK, Caligiuri, MA, Cao, L. CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice. Aging (Albany NY) 2020 12:2101-2122. PubMed PMID: 32007953 DOI: 10.18632/aging.102724.
4. Mitigating aging-related metabolic decline and cancer growth. Aging, metabolic dysfunction, and cancer risk are inextricably intertwined. We recently report that implementing environmental enrichment in middle-age mice mitigates age-related deficiencies in metabolic function and thus slows Lewis lung carcinoma growth. We are currently expanding this research to triple-negative breast cancer that is associated with increased risk and poor prognosis in postmenopausal females.
a. Queen, NJ, Deng, H, Huang, W, Mo, X, Wilkins, RK, Zhu, T, Wu, X, Cao, L. Environmental enrichment mitigates age-related metabolic decline and Lewis lung carcinoma growth in aged female mice. Cancer Prev Res 2021 Sep 17. Online ahead of print. PubMed PMID: 34535449 DOI: 10.1158/1940-6207.CAPR-21-0085.
b. Hassan, QN 2nd, Queen, NJ, Cao, L. Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis. Tranl Cancer Res 2020 Sep;9(9), 5687-5699. PubMed PMID: 33124111 DOI: 10.21037/tcr.2020.02.39
5. Identifying brain mediators distinguishing eustress and distress impact on metabolism and cancer. Epidemiological studies have revealed that social support is linked to improved health outcomes among cancer patients whereas social isolation predicts risk for mortality. We are using a multidisciplinary approach to provide a comprehensive and explicit comparison between the eustress model environmental enrichment versus distress model social isolation on cancer, metabolism, and immunity.
a. Cao, L, During, MJ. What is the brain-cancer connection? Annu Rev Neurosci 2012, 35, 331-345. PubMed PMID: 22462541 DOI: 10.1146/annurev-neuro-062111-150546
6. Gene therapy of obesity and metabolic syndromes. We have developed a built-in auto-regulatory system to control therapeutic gene BDNF expression mimicking the body’s natural feedback systems. This patented technology leads to a sustainable plateau of body weight after substantial weight loss is achieved in genetic model of diabetes db/db mice, as well as melanocortin-4-receptor deficient mice, a model for the most common monogenic form of obesity in humans. Currently, we are investigating the therapeutic efficacy and safety of this autoregulatory BDNF gene therapy in a murine model of Prader-Willi Syndrome.
a. Cao, L, Lin, EJ, Cahill, MC, Wang, C, Liu, X, During, MJ. Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nature Medicine 2009, 15, 447-54. PubMed PMID: 19270710; PubMed Central PMCID: PMC3900280.
b. Siu, JJ, Queen, NJ, Liu, X, Huang, W, McMurphy, T, Cao, L. Molecular therapy of melanocortin-4-receptor obesity by an autoregulatory BDNF vector. Mol Ther Methods Clin Dev 2017, Sep 29;7:83-95. PubMed PMID: 29296625; DOI: 10.1016/j.omtm.2017.09.005.
c. Matthew During and Lei Cao. Treatment of metabolic-related disorders using hypothalamic gene transfer of BDNF and compositions therefor. U.S. Patent 9,265,843 B2. 02/23/2016. (The Ohio State University)
d. McMurphy, T, Huang, W, Liu, X, Siu, JJ, Queen, NJ, Xiao, R, Cao, L. Hypothalamic gene transfer of BDNF promotes healthy aging in mice. Aging Cell 2019: e12846. PubMed PMID: 30585393; DOI: 10.111/acel.12846
7. Adipose-targeting adeno-associated virus (AAV) vector development. We have characterized a novel engineered serotype that is the most efficient rAAV vector for fat. Moreover, we have developed a dual-cassette vector system that transduces the visceral fats while eliminating off-target transduction of liver (patent pending), and have demonstrated its specificity, efficacy, and therapeutic potentials in models of obesity and cancer immunotherapy. Developing AAV platform for adipose-oriented gene transfer and gene therapy remains a major research area of the lab.
Comparison of transduction efficiency of novel engineered AAV serotypes with natural serotypes in white fat. (a) GFP immunohistochemistry of IWAT 4 weeks after rAAV injection. Scale bar = 100 µm. (b) GFP immunofluorescence of AAV8- and Rec2-injected IWAT (pictures were taken with the same exposure) and GFP fluorescence of liver, kidney, and skeletal muscle adjacent to IWAT. Scale bar = 50 µm. AAV, adeno-associated virus; GFP, green fluorescent protein; IWAT, inguinal white adipose tissue; rAAV, recombinant AAV.
a. Liu, X, Magee, D, Wang, C, McMurphy, T, Slater, A, During, M, Cao, L. Adipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype. Mol Ther Methods Clin Dev 2014, 1, 8; PubMed PMID: 25383359; PubMed Central PMCID: PMC4224270.
b. Huang, W, McMurphy, T, Liu, X, Wang, C, Cao, L. Genetic Manipulation of brown fat via oral administration of an engineered recombinant adeno-associated viral serotype vector. Molecular Therapy 2016, 24, 1062-1069. PubMed PMID: 26857843; PubMed Central PMCID: PMC4923319.
c. Huang, W, Queen, NJ, McMurphy, TB, Ali, S, Cao, L. Adipose PTEN regulates adult adipose tissue homeostasis and redistribution via a PTEN-leptin-sympathetic loop. Mol Metab 2019, 30, 48-60. PubMed PMID: 31767180; DOI: 10.1016/j.molmet.2019.09.008
d. Xiao, R, Mansour, AG, Huang, W, Chrislip, LA, Wilkins, RK, Queen, NJ, Youssef, Y, Mao, HC, Caligiuri, MA, Cao, L. Adipocytes: A novel target for IL-15/IL-15Ra cancer gene therapy. Molecular Therapy 2019, 27, 922-932. PubMed PMID: 30833178; DOI: 10.1016/j.ymthe.2019.02.011