September 7, 2020 – Like wrenches made of Legos, SWI/SNF chromatin remodeling complexes tighten or loosen DNA in our cells…
The link between cancer and organ regeneration is poorly understood. While many cancers develop as a consequence of chronic injury, it’s unclear if a strong regenerative capacity protects or promotes tumor formation. For example, too much regeneration causes organ overgrowth and potentially cancer while too little results in impaired organ function, fibrosis and eventually an environment for cancer outgrowth.
Our lab is interested in understanding the relationship between injury, regeneration and cancer. We are focused on identifying the genes and mechanisms that regulate regenerative capacity in the liver and understanding how these contribute to hepatocellular carcinoma development – the third leading cause of cancer death in the world. Using mouse models developed in our lab that have improved regenerative capacity, we are examining the underlying mechanisms and inherent limitations of regeneration in mammals. Doing so could lead to treatment options that could promote tissue regeneration and prevent or delay cancer.
Reactivation of Embryonic RNA-Metabolism Growth Programs in HCC and Cholangiocarcinoma
Understanding and Augmenting Liver Regeneration by Dissecting Epigenetic Mechanisms
Understanding the Influence of Regenerative Capacity on Cancer
Heterochronic genes encode products whose expression changes throughout time in tissues and temporally regulates developmental changes, organ growth and regenerative capacity. For example, many heterochronic genes are expressed in fetal, but not adult, tissues such that they promote the rapid growth of fetal tissues and are shut off postnatally. Cancers can reactivate these heterochronic genes in adult tissues to enable neoplastic proliferation. We have uncovered important roles for heterochronic genes by using murine models that allow temporally specific gain or loss of Lin28 and let-7.
Recently, we showed that adult reactivation of Lin28a promotes regeneration capabilities reminiscent of embryonic tissue (Nguyen et. al., 2014). Lin28’s ability to temporally integrate embryonic metabolism, cell proliferation and tissue growth also contributes to its oncogenic activities. We are currently determining the functions and mechanisms of the oncofetal RNA-binding protein Imp3 (aka Igf2bp3), a well-known downstream target of let-7 and Lin28. Our goal is to define the mechanisms downstream of Imp3 that are therapeutically relevant.
Epigenetic machines reprogram genomic structure, gene expression and cellular functions during tissue regeneration. It is unknown how this machinery influences regenerative capacity in any tissue system. The liver is the ideal context in which to unravel these longstanding questions. We discovered that Arid1a, a component of the SWI/SNF ATP-dependent chromatin-remodeling complex, plays critical roles in liver injury and regeneration (Sun et. al., 2016). Chromatin structure is remodeled during regeneration to alter accessibility for transcription factors that alter cell fate and function such that lost tissues can be replenished. We showed that liver-specific Arid1a knockout mice have enhanced regeneration after multiple forms of surgical, chemical and genetic injury.
For the first time, these findings connect chromatin-remodeling machinery with organ regeneration and suggest that we have only uncovered the “tip of the iceberg” in terms of understanding the epigenetic mechanisms regulating regeneration. Currently, we are examining how this chromatin-remodeling complex controls gene expression and regeneration on the molecular level.
Understanding the Influence of Regenerative Capacity on Cancer
It is widely assumed that cancer risk increases with regenerative capacity, but we expect the relationship is more complicated. In mammals, chronic organ damage in the skin, lung, intestine and liver is strongly associated with cancer, but it is possible that the potent regenerative abilities of these organs serve to preserve tissue integrity, reduce inflammation and resist transformation in the context of recurrent injury. Causative mechanisms have been difficult to study because animals with different regenerative capabilities are often evolutionarily or genetically distant. A general strategy is to develop mice that possess enhanced or altered organ regeneration in order to understand how modulating regeneration influences carcinogenesis in the liver.
This work is inspired by the clinical problem of hepatocellular carcinoma (HCC), a malignancy that arises from a highly regenerative organ that experiences recurrent injury. Although HCC is the third leading cause of cancer death in the world, scientific understanding of HCC is limited — a fact that our inability to predict outcomes, much less treat advanced cases, reflects. A goal for our lab is to understand how influences on regeneration may be employed to control cancer development.
About Dr. Zhu
Hao Zhu earned his bachelor’s degree in biology from Duke University, followed by an M.D. from Harvard Medical School and MIT. He underwent training in internal medicine at University of California, San Francisco and medical oncology at the Dana-Farber Cancer Institute. From 2008 to 2012, Dr. Zhu performed postdoctoral research at Boston Children’s Hospital, where he explored connections among RNA biology, cancer and regeneration in mouse models. In 2012, he joined the faculty of the Children’s Medical Center Research Institute at UT Southwestern. He is also an attending physician in the Multidisciplinary Liver Cancer Clinic at Parkland Memorial Hospital.
Dr. Zhu is the recipient of a Burroughs Wellcome Career Award for Medical Scientists (2012), a CPRIT Scholar Award (2012) and a Stand Up To Cancer Innovative Research Grant (2016).
Lin, Y.H., Zhang, S., Zhu, M., Lu, T., Chen, K., Wen, Z., Wang, S., Xiao, G., Luo, D., Jia, Y., Li, L., MacConmara, M., Hoshida, Y., Singal, A., Yopp, A., Wang, T., and Zhu, H. (2020). Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity but Develop Fewer Tumors Following Chronic Liver Injury. Gastroenterology. Epub ahead of print. (PubMed)
Zhu,.M., Li, L., Lu, T., Yoo, H., Zhu, J., Gopal, P., Wang, S.C., Porempka, M.R., Rich, N.E., Kagan, S., Odewole, M., Renteria, V., Waljee, A.K., Wang, T., Singal, A.G., Yopp, A.C., and Zhu, H. (2020). Uncovering biological factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays. Hepatology. Epub ahead of print. (PubMed)
Zhu, M., Lu, T., Jia, Y., Luo, X., Gopal, P., Li, L., Odewole, M., Renteria, V., Singal, A.G., Jang, Y., Ge, K., Wang, S.C., Sorouri, M., Parekh, J.R., MacConmara, M.P., Yopp, A.C., Wang, T., and Zhu, H. (2019). Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease. Cell. 177, 1-14. (PubMed)
Moore, A., Wu, L., Chuang, J.C., Sun, X., Luo, X., Gopal, P., Li, L., Celen, C., Zimmer, M., and Zhu, H. (2018) Arid1a loss drives non-alcoholic steatohepatitis in mice via epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation. Hepatology. 61, 1931-1945. (PubMed)
Wang, S.C., Nassour, I., Xiao, S., Zhang, S., Luo, X., Lee, J., Li, L., Sun, X., Nguyen, L.H., Chuang, J.C., Peng, L., Daigle, S., Shen, J., and Zhu H. (2018). SWI/SNF component ARID1Arestrains pancreatic neoplasia formation. Gut. 68, 1259-1270.(PubMed)
Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.C., Sehgal, A., Nguyen, L.H., Zhang, Yu., Gopal, P., Tarlow, B., Siegwart, D.J., and Zhu, H. (2018). The polyploid state plays a tumor suppressive role in the liver. Developmental Cell. 44, 447-459. (PubMed)
Zhang, S., Nguyen, L.H., Zhou, K., Tu, H.C., Sehgal, A., Nassour, I., Li, L., Gopal, P., Goodman, J., Singal, A.G., Yopp, A., Zhang, Y., Siegwart, D.J., and Zhu, H. (2017). Knockdown of Anillin Actin Binding Protein Blocks Cytokinesis in Hepatocytes and Reduces Liver Tumor Development in Mice without Affecting Regeneration. Gastroenterology. 154, 1421-1434. (PubMed)
Sun, X.*, Wang, S.C.*, Luo, X., Jia, Y., Li, L., Gopal, P., Zhu, M., Nassour, I., Chuang, J.C., Maples, T., Celen, C., Nguyen, L.H., Wu, L., Fu, S., Li, W., Hui, L., Tian, F., Ji, Y., Zhang, S., Sorouri, M., Hwang, T.H., Letzig, L., James, L., Yopp, A., Singal, A., and Zhu, H. (2017). Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell. 32, 574-589. (PubMed) *Equal contributors.
Celen, C., Chuang, J.C., Luo, X., Nijem, N., Walker, A.K., Chen, F., Zhang, S., Chung, A.S., Nguyen, L.H., Nassour, I., Budhipramono, A., Sun, X., Bok, L.A., McEntagart, M., Gevers, E.F., Birnbaum, S.G., Eisch, A.J., Powell, C.M., Ge, W.P., Santen, G.W., Chahrour, M., and Zhu, H. (2017). Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. eLife. e25730. (PubMed)
Sun, X., Chuang, J.C., Kanchwala, M., Wu, L., Celen, C., Li, L., Liang, H., Zhang, S., Maples, T., Nguyen, L.H., Wang, S.C., Signer, R.A., Sorouri, M., Nassour, I., Liu, X., Xu, J., Wu, M., Zhao, Y., Kuo, Y.C., Wang, Z., Xing, C., and Zhu, H. (2016). Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration. Cell Stem Cell 18, 456–466. (PubMed)
Wu, L.*, Nguyen, L.H.*, Zhou, K., Soysa, T.Y., Li, L., Miller, J.B., Tian, J., Locker, J., Zhang, S., Shinoda, G., Seligson, M.T., Zeitels, L.R., Acharya, A., Wang, S.C., Mendell, J.T., He, X., Nishino, J., Morrison, S.J., Siegwart, D.J., Daley, G.Q., Shyh-Chang, N., and Zhu, H. (2015). Precise Let-7 expression levels balance organ regeneration against tumor suppression. eLife 4:e09431. (PubMed) *Equal contributors
Nguyen, L.H.*, Robinton, D.A.*, Seligson, M.T.*, Wu, L., Li, L., Rakheja, D., Comerford, S.A., Ramezani, S., Sun, X., Parikh, M.S., Yang, E.H., Powers, J.T., Shinoda, G., Shah, S.P., Hammer, R.E., Daley, G.Q.,** and Zhu, H.**. (2014). Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 26, 248–261. (PubMed) *Equal contributors. **Co-corresponding authors.
Jen-Chien Chuang, Ph.D.
Assistant Instructor (2014-2016)
Xin Luo, Ph.D.
Data Scientist (2016-2018)
Ibrahim Nassour, M.D.
Clinical Fellow, Surgery (2015-2017)
Liem Nguyen, Ph.D.
Ph.D. Student (2013- 2017)
Shunli Shen, M.D., Ph.D.
Visiting Scholar (2018)
XuXu Sun, Ph.D.
Postdoctoral Fellow (2013-2019)
Linwei Wu, Ph.D.
Visiting Scholar (2013–2015)
Ph.D. Student (2013-2018)