Iok In Christine Chio, PhD

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Overview

Academic Appointments

  • Assistant Professor of Genetics & Development at the Institute for Cancer Genetics

Dr. Christine Chio is a new junior faculty at the Institute of Cancer Genetics. Dr. Chio received her PhD from the University of Toronto under the mentorship of Dr. Tak Wah Mak, studying the interplay between inflammation and cancer development. Subsequently, she joined the lab of Dr. David Tuveson at Cold Spring Harbor Laboratory to pursue her postdoctoral training. Since then, her research endeavor has focused on understanding the role of cellular redox regulation, particularly in the development of pancreatic ductal adenocarcinoma (PDA). 

A key histopathological feature of PDA that is also associated with its innate clinical and biological aggressiveness is its pronounced desmoplastic (stromal) reaction. Desmoplasia generates a nutrient and oxygen-deprived environment in PDA that is unique to the disease. The resultant redox and metabolic adaptations thus create cancer-specific vulnerabilities that could potentially be exploited. The central hypothesis of the Chio lab is that PDA cells harness reactive oxygen species (ROS) as selective secondary messengers to support cancer cell viability and tumor-stroma co-evolution. The goal of her research is to leverage the ability of PDA cells to regulate levels of ROS towards the development of more effective therapies for this highly lethal malignancy. The cytoprotective transcription factor NRF2 is a central regulator of redox homeostasis and is up-regulated in PDA. As transcription factors are difficult to target therapeutically, the Chio laboratory seeks to comprehensively characterize the mechanisms used by NRF2 to promote PDA such that more feasible approaches to counter its effects in PDA may be developed. In pursuit of this goal, genetically engineered mouse models (GEMM), ex-vivo organoid co-culture systems, and patient-derived organoid transplantation models will be used to establish a discovery pipeline and in vivo validation platforms that will facilitate the design of integrated intervention strategies for a disease involving complex interactions between the tumor and the stroma.

Languages

  • Cantonese
  • Mandarin

Gender

  • Female

Credentials & Experience

Education & Training

  • PhD, 2012 Medical Biophysics, Princess Margaret Hospital Toronto

Honors & Awards

2003, 2004, 2005: University of Toronto Scholar award
2003, 2004, 2005: University of Toronto, St. Michael’s College in course scholarship
2004: Charles Lester Mills Scholarship in Science
2004, 2005: Pang Shou Yun scholarship
2005: Life science Fellowship (U of T, Dept of Medical Genetics)
2005: Starbucks Clinical Genetics Studentship (Hospital of Sick children)
2006: University of Toronto, St Michael’s College Silver Medal (Graduation award for student with high cGPA)
2006, 2007, 2008: University of Toronto Fellowship
2006-2011: University of Toronto Connaught Scholarship
2009: 12th International TNF conference award
2009, 2010: Ontario Graduate Scholarship (OGS 2009-2010)
2011, 2012: Medical Biophysics Excellence Award
2012-2013: Human Frontiers post doctoral fellowship
2013-2017: Damon Runyon post doctoral fellowhip
2003-Present: Member of Golden Key International Honour Society
10/2013- Present: Damon Runyon Research Fellow
7/2016: Aspen Cancer Fellowship
4/2015-Present: Member of American Association for Cancer Research
2/2017-Present: Editorial board member of “Gastroenterology and Liver Clinical and Medical Issues”

Research

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer death in the United States. Lethality of PDA owes largely to the advanced disease stage at the time of diagnosis and to its profound resistance to existing therapies. Targeted therapy is a cornerstone of precision medicine, and is currently the focus of much anticancer drug development. However, in the context of pancreatic cancer, no chemical inhibitors exist for the most common KRAS mutations (G12D, G12V) even though it is well established that the oncogenic KRAS promotes drug resistance. Thus, a detailed understanding of the role of specific genetic lesions and their signaling surrogates in the initiation and progression of PDA is critical to improving treatment efficacy and patient outcome for this disease.

Our goal is to utilize sophisticated genetically engineered mouse models and ex vivo culture systems to understand the basic mechanisms underlying PDA redox biology such that vulnerabilities can be identified and tested for therapeutic intervention. 

More about our work:

http://cancerdiscovery.aacrjournals.org/content/6/9/945.2

https://aimsci.com/ros/index.php/ros/article/view/61

http://www.sciencedirect.com/science/article/pii/S1471491417300436

http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(17)30043-6

Research Interests

  • preclinical therapeutics in genetically engineered mouse models of pancreatic cancer
  • redox biology
  • cancer metabolism
  • ex vivo 3D organoid platforms to study pancreatic cancer

Grants

TARGETING REDOX STATUS AND MRNA TRANSLATION IN PANCREATIC CANCER (Private)

Jul 1 2018 - Jun 30 2021

CLINICAL TRANSLATION OF REGULATORY NETWORK-BASED PRECISION MEDICINE FOR PANCREATIC CANCER (Private)

Apr 1 2018 - Mar 31 2021

TARGETING REDOX-DEPENDENT PROTEIN SYNTHESIS IN KRAS-DRIVEN CANCERS (Private)

Nov 1 2018 - Nov 1 2020

METABOLIC PROFILING TO IDENTIFY KEY REGULATORY EVENTS THAT DRIVE PANCREATIC TUMORIGENESIS AND METASTATIC DISSEMINATION (Private)

Jun 1 2019 - May 31 2020

Selected Publications

Corresponding author publications

Chio, II, Tuveson DA. ROS in Cancer: The Burning Question. Trends in Molecular Medicine. 2017. 2017; 23(5):411-429

First author publications

Chio, II, Tuveson DA. ROS in translation: chink in the armor. Cell cycle. 2016

Chio, II, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K, Palm W, Wilson J, Sangar V, Hao Y, Ohlund D, Wright K, Filippini D, Lee EJ, Da Silva B, Schoepfer C, Wilkinson JE, Buscaglia JM, DeNicola GM, Tiriac H, Hammell M, Crawford HC, Schmidt EE, Thompson CB, Pappin DJ, Sonenberg N, Tuveson DA. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell. 2016;166(4):963-76.

Boj SF*, Hwang CI*, Baker LA*, Chio, II*, Engle DD*, Corbo V*, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH, van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Ohlund D, Handly-Santana A, Ardito-Abraham CM, Ludwig M, Elyada E, Alagesan B, Biffi G, Yordanov GN, Delcuze B, Creighton B, Wright K, Park Y, Morsink FH, Molenaar IQ, Borel Rinkes IH, Cuppen E, Hao Y, Jin Y, Nijman IJ, Iacobuzio-Donahue C, Leach SD, Pappin DJ, Hammell M, Klimstra DS, Basturk O, Hruban RH, Offerhaus GJ, Vries RG, Clevers H, Tuveson DA. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160(1-2):324-38.

*Authors contributed equally to work.

Chio, II, Yordanov G, Tuveson D. MAX-ing out MYC: a novel small molecule inhibitor against MYC-dependent tumors. JNCI. 2014;106(12).

Chio, II, Sasaki M, Ghazarian D, Moreno J, Done S, Ueda T, Inoue S, Chang YL, Chen NJ, Mak TW. TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation. Nat Cell Biol. 2012;14(6):625-33.

Chen NJ*, Chio, II*, Lin WJ, Duncan G, Chau H, Katz D, Huang HL, Pike KA, Hao Z, Su YW, Yamamoto K, de Pooter RF, Zuniga-Pflucker JC, Wakeham A, Yeh WC, Mak TW. Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors. Proc Natl Acad Sci U S A. 2008;105(34):12429-34.

*Authors contributed equally to work

Co-author publications

1.     Tonelli C, Chio II, Tuveson DA. Transcriptional regulation by Nrf2. Antioxidants & redox signaling. 2017. In Press.

Liberti MV, Dai Z, Wardell S, Baccile J, Liu XJ, Gao X, Baldi R, Mehrmohamadi M, Johnson MO, Madhukar NS, Shestov AA, Chio II, Tuveson D, Elemento O, Rathmell JC, Schroeder FC, McDonnell D and Locasale J. Selective targeting of the Warburge ffect and precision medicine from metabolic control analysis. Cell Metabolism. 2017. Cell metabolism. 2017; 26(4):648-659

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Aameida A, Ponz-Sarvise M, Corbo V, Oni T, Hearn S, Lee EJ, Chio II, Hwang CI, Tiriac H, Baker L, Engle D, Egeblad M, Fearon D, Crawford J, Clevers H, Park Y, Tuveson D. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017.  2017; 214(3):579-596

Dominguez-Brauer C, Hao Z, Elia AJ, Fortin JM, Nechanitzky R, Brauer PM, Sheng Y, Mana MD, Chio, II, Haight J, Pollett A, Cairns R, Tworzyanski L, Inoue S, Reardon C, Marques A, Silvester J, Cox MA, Wakeham A, Yilmaz OH, Sabatini DM, van Es JH, Clevers H, Sato T, Mak TW. Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation. Cell Stem Cell. 2016;19(2):205-16.

Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, Roper J, Chio, II, Giannopoulou EG, Rago C, Muley A, Asara JM, Paik J, Elemento O, Chen Z, Pappin DJ, Dow LE, Papadopoulos N, Gross SS, Cantley LC. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350(6266):1391-6.

Itsumi M, Inoue S, Elia AJ, Murakami K, Sasaki M, Lind EF, Brenner D, Harris IS, Chio, II, Afzal S, Cairns RA, Cescon DW, Elford AR, Ye J, Lang PA, Li WY, Wakeham A, Duncan GS, Haight J, You-Ten A, Snow B, Yamamoto K, Ohashi PS, Mak TW. Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Cell Death Differ. 2015;22(11):1837-45.

Naguib A, Bencze G, Engle DD, Chio, II, Herzka T, Watrud K, Bencze S, Tuveson DA, Pappin DJ, Trotman LC. p53 mutations change phosphatidylinositol acyl chain composition. Cell Reports. 2015;10(1):8-19.

Chang YL, Chen TH, Wu YH, Chen GA, Weng TH, Tseng PH, Hsieh SL, Fu SL, Lin CH, Chen CJ, Chu CL, Chio, II, Mak TW, Chen NJ. A novel TLR2-triggered signalling crosstalk synergistically intensifies TNF-mediated IL-6 induction. J Cell Mol Med. 2014;18(7):1344-57.

Inoue S, Hao Z, Elia AJ, Cescon D, Zhou L, Silvester J, Snow B, Harris IS, Sasaki M, Li WY, Itsumi M, Yamamoto K, Ueda T, Dominguez-Brauer C, Gorrini C, Chio, II, Haight J, You-Ten A, McCracken S, Wakeham A, Ghazarian D, Penn LJ, Melino G, Mak TW. Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes Dev. 2013;27(10):1101-14.

Berger T, Ueda T, Arpaia E, Chio, II, Shirdel EA, Jurisica I, Hamada K, You-Ten A, Haight J, Wakeham A, Cheung CC, Mak TW. Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene. 2013;32(41):4989-94.

Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio, II, Cairns RA, McCracken S, Wakeham A, Haight J, Ten AY, Snow B, Ueda T, Inoue S, Yamamoto K, Ko M, Rao A, Yen KE, Su SM, Mak TW. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 2012;26(18):2038-49.

Lin WJ, Su YW, Lu YC, Hao Z, Chio, II, Chen NJ, Brustle A, Li WY, Mak TW. Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunity. Proc Natl Acad Sci U S A. 2011;108(45):18354-9.

Ueda T, Sasaki M, Elia AJ, Chio, II, Hamada K, Fukunaga R, Mak TW. Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc Natl Acad Sci U S A. 2010;107(32):13984-90.