Faculty / Research

Chia-Hsin (Lori) Chan, PhD

Associate Professor 

 

Ph.D.: National Taiwan University, Taiwan

Postdoctoral Fellowship: University of Texas MD Anderson Cancer Center

Basic Science Tower 8-121
631-444-3085/office  chia-hsin.chan@stonybrook.edu
Cancer stem cells and drug resistance; dysregulated metabolism in cancer stemness and tumor immunity; E3 ubiquitin ligase and targeted therapeutics.

 

Tumor heterogeneity is frequently displayed in human cancers. This phenotype can be attributed to two mechanisms–cancer cell clonal evolutions and propagation of cancer stem cells (CSCs). CSCs, despite of the rareness, are known as a major contributor for drug resistance, tumor relapse and consequently cancer death. Two hallmarks of cancer are known to orchestrate CSC dormancy and reaction: 1) Epithelial-mesenchymal transition (EMT) and 2) Dysregulated metabolism. My laboratory focuses on deciphering regulatory machinery and mechanism (e.g. E3 ubiquitin ligase and ubiquitination, metabolic enzymes and drivers, etc.) responsible for EMT and dysregulated metabolism in cancer cells and CSCs. Besides the neoplastic cancer cells, lymphocytes and macrophages are prominent residents in tumor microenvironment. My laboratory also investigates the mechanisms underlying the tumor immunity. The ultimate goal is to develop the mechanism-based cancer therapeutics. We use complementary approaches including cell biological and biochemical methods, informatics tools, animal models (xenograft, syngeneic, genetically-modified, PDX and humanized mice), and clinical specimens to interrogate the following research projects:

1)  To delineate the network of metabolic reprogramming in tumor initiation and progression. Glucose and glutamine are the most rapidly consumed nutrients by cancer cells. Recent studies have revealed a high degree of metabolic plasticity in human cancers in terms of tumor cell nutrient utilization. Aside from glucose, many cancer cells display oncogene addiction to glutamine metabolism. Glutamine not only serves as a carbon and nitrogen source in cancer cells for macromolecule biosynthesis and for energy production but it also regulates signaling pathways and maintains redox homeostasis, contributing to cancer cell proliferation and survival. In contrast to the increasing knowledge about glucose and glutamine regulation in fast-cycling cancer cells, whether and how these nutrients affects CSC phenotypes and functions remains largely unknown. We are currently identifying the genetic alterations and mechanisms that underlie the glucose and/or glutamine dependency of cancer cells as well as CSCs. The knowledge would have important implications for basic science and for metabolism-based targeted therapies. Results from this research program had led to several research articles including those published in Cell (2012) and Nat Commu. (2019).

 

2) To explore regulatory machinery orchestrating EMT-driven cancer stemness and drug resistance. The CSC population preferably stays in quiescence stage (G0 phase) and thus adversely sensitizes to chemo- or radio-therapies. Epithelial to mesenchymal transition (EMT) program is responsible for cancer progression, drug resistance and recently is engaged in acquiring CSC properties. Thus, my research is to decode regulatory network of EMT, which will identify new strategies to eliminate CSC population and overcome drug resistance. Our research program has led to several highly regarded publications in Cell (2013), Molecular Cell (2016), Oncogene (2017), Cell Death & Dis (2019), etc and were highlighted in Nat. Review Cancer, Nat. Review Drug Discovery, Cancer Discovery, Nat. Review of Urology and newspapers. 

 

3) Development of small molecule inhibitors targeting glycolysis or EMT as new therapeutic interventions. Once novel targets for cancer prevention have been identified as described above, I will use in silico screening to develop novel therapeutic arsenals accordingly. This research program is expected to identify effective inhibitors that are anticipated to overcome drug resistance and prolong tumor remission through targeting glycolysis or EMT. 

 

4) To elucidate the role of tumor-derived metabolites in tumor microenvironment and anti-tumor immunity. Tumor microenvironment (TME) is composed of tumor cells, stromal cells and immune cells. Elevated glucose and glutamine uptake consumption in cancer cells is known causes nutrient dearth in the niches that is known to suppress anti-tumor immunity. We are currently characterizing the mechanism by which tumor cell metabolism regulating proteins impedes the responses and activities of tumor-associated microphages and cytotoxic lymphocytes.

For a complete list of current publications please click HERE.

Selected publications (#First, *Corresponding author):  3200 citations; h-index=25; h-10 index= 28 

  1. Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, Yang WL, Erdjument-Bromage H, Nimer S, Tempst P, Pandolfi PP (2009) Phosphorylation-dependent regulation of Skp2 cytosolic localization oncogenic function by Akt/PKB. Nat. Cell Biol. 11:420-432

2. Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Hur L, Grabiner B, Lin X, Darnay B, Lin HK    (2009). The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325:1134-1138.

Highlight by DF Restuccia and BA Hemmings in (2009) in Science 325:1083-4.

3. Lin HK, Chen Z, Wang G, Lee SW, Wang J, Chan CH, Yang WL, Nakayama KI, Cordon-Cardo C,Teruya-Feldstein J, Pandolfi PP (2010). Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature (Article), 464, 374-379.

4. #Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY, Wu J, Nakayama KI, Kang HY, Huang HY, Hung MC, Pandolfi PP, Lin HK (2010) Deciphering the transcription complex critical for RhoA gene expression and cancer metastasis. Nat. Cell Biol. (Article), 12, 457-467

5.  Wu J, Zhang X, Zhang L, Wu CY, Rezaelan AH, Chan CH, Li JM, Wang J, Gao Y, Fei H, Jeong YS, Yuan X, Khanna KK, Jin J, Zeng YX, Lin HK (2012) Skp2 E3 ligase integrates ATM activation and         homologous recombination repair by ubiquitinating NBS1. Molecular Cell 46: 351-61

6. #Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Huang HY, Tsai KT, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung, MC, Nakayama KI, Lin HK (2012). The Skp2 E3 ubiquitin ligase regulates Akt ubiquitination, glycolysis, Herceptin sensitivity and tumorigenesis. Cell 149: 1098–1111     

7. #Chan CH, Morrow JK, Li CF,  Gao Y, Jin G, Moten A, Stagg LJ, Ladbury JE, Cai Z, Xu D, Logothetis CJ, Hung MC, Zhang S*, Lin HK (2013). Pharmacological Skp2 inactivation restricts cancer stem cell traits and cancer progression. Cell 154:556-68.

Research highlights by Sarah Seton-Rogers (2013) Nature Review Cancer 13, 609

Research highlights by Charlotte Harrison (2013) Nature Review Drug Discovery 12, 740-741

Research highlights in Cancer Discovery 3(10), OF30 

8. Wagner, KW, Alam H, Dhar, SS, Giri U, Li N, Wei Y, Giri D, Cascone T, Kim JH, Ye Y, Multani A, Chan CH,  Erez B, Saigal B, Chung J,  Lin HK, Wu X, Hung MC, Heymach JV, Lee MG (2013). KDM2A Activates ERK1/2 via DUSP3’s Epigenetic Repression and promotes NSCLC. Journal of Clinical Investigation 123: 5261-46

       9.  Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH, Yang WL, Li BK, Rezaeian AH, Li HY, Huang HY, Lin HK (2015). Skp2-Dependent Ubiquitination and Activation of LKB1 Is Essential for Cancer Cell Survival under Energy Stress. Molecular Cell 57: 1022-33

10. Xu D, Li CF, Zhang X, Gong Z, Chan CH, Lee SW, Jin G, Rezaeian AH, Han F, Wang J, Yang WL, Feng ZZ, Chen W, Wu CY, Wang YJ, Chow LP, Zhu XF, Zeng YX, Lin HK.(2015) Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nature Communications 6:6641  

11.  Jin G, Lee SW, Zhang X, Cai Z, Gao Y, Chou PC, Rezaeian AH, Han F, Wang CY, Yao JC, Gong Z, Chan CH, Huang CY, Tsai FJ, Tsai CH, Tu SH, Wu CH, Sarbassov dos D, Ho YS, Lin HK. (2015) Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. Molecular Cell 58:989-1000

12. Lee HJ, Li CF, Ruan D, Powers S, Thompson PA, Frohman MA, Chan CH*. (2016) The DNA damage transducer RNF8 facilitates cancer chemoresistance and progression through Twist activation Molecular Cell (Featured Article) 63(6):1021-33 *Corresponding author  

Research highlights by Krista L. Bledsoe in Cancer Discovery. DOI: 10.1158/2159-8290.CD-RW2016-173 

13. Mladinich M, Ruan D, and Chan CH*. (2016) Current advances and future perspective of EMT-based therapy in targeting cancer stem cells. Stem Cells International vol. 2016, Article ID 5285892, doi:10.1155/2016/5285892.

14. Ruan D, He J, Lee HJ, Liu J, Lin HK and Chan CH* (2017) Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist. Oncogene 36: 4299-4310 Research highlights by Annette Fenner in Nature Reviews Urology (2017) vol. 14, p387

15. He J, Lee HJ, Saha S, Ruan D, Guo H and Chan CH* (2019). Inhibition of USP2 eliminates cancer stem cells and sensitizes TNBC to chemotherapy through disrupting the Twist/Bmi1 pathway. Cell Death & Disease 10:285-300

Press release by Newsday and Times Beacon Record Newspapers

Research highlights in Stony Brook News, Futurity, HealthNewsDigest.com, and BIOPHARMA. 

16. Lee HJ, Li CF, Ruan D, He J, Montal ME, Lorenz S, Girnun GD, Chan CH* (2019) Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumorigenesis, energy metabolism and cancer stem cell expansion. Nature Communications 10:2625 *Corresponding author

 

Highlight as a Top Story in Prostate Cell News Vol. 10.21/June 14, 2019

       
Patent
1. Zhang S, Lin HK, Chan CH, Morrow JK. Small Molecule Inhibitors Targeting the SKP2 Pathway for Cancer Treatment. US Provisional Patent application. (PATENT UTSC.P1114US.P1)



Research Group

 

Hong-Jen (Joshua) Lee
Senior Postdoctoral Associate
PhD: UT MD Anderson Cancer Center, TX
Hong-Jen.Lee@stonybrook.edu 


Yi-Jye (EJ) Chern

Postdoctoral Associate
PhD: University of British Columbia, Vancouver, British Columbia, Canada
yi-jye.chern@stonybrook.edu

 

Jiabei He

Graduate student (MCP PhD Program)

AACR associate member and selected poster presenter

MS: Stony Brook University

jiabei.he.1@stonybrook.edu

 

Bruno Carvalho

Graduate student (MCP PhD Program)

Latin America Scholarship Program of American Universities (LASPAU), 2014-2018

MS: State University of New York (SUNY) at Albany 

bruno.pereiradecarvalho@stonybrook.edu

 

Golbahar Sadatrezaei

Graduate student (MCP Master Program)

BS: Stony Brook University

golbahar.sadatrezaei@stonybrook.edu

Chia-Hsin (Lori) Chan Ph.D.
Associate Professor
Department of Pharmacological Science
Basic Science Tower 8-121
Stony Brook University 
Stony Brook, NY 11794-8651
Phone: 631-444-3085 (Office); 631-444-9743 (Lab)

E-Mail: chia-hsin.chan@stonybrook.edu