Chih-Chi Andrew Hu, Ph.D.

faculty photo
Wistar Institute Associate Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
Immunology, Microenvironment & Metastasis Program, Wistar Institute, Room 430, 3601 Spruce Street
Philadelphia, PA 19104-4265
Office: 215-495-6976
Lab: 215-898-3768
MS (Pharmacology)
New York University School of Medicine, 2004.
PhD (Pharmacology)
New York University School of Medicine, 2006.
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Description of Research Expertise

Research Interest:
The biology of the endoplasmic reticulum in health and disease

Endoplasmic reticulum (ER); B cell; protein folding and assembly; glycosylation; membrane protein trafficking

Research Details:
We are fascinated by the endoplasmic reticulum (ER), which has critical functions in lipid synthesis, calcium storage and drug metabolism. The ER also contains complex machineries to fold, assemble, transport or –as the need arises- destruct many vital integral membrane growth receptors and secretory proteins. The complexity of the ER functions attracts us to understand it better.

We studied the ER functions in B cells because differentiated B cells produce a dramatically expanded ER for the production and secretion of antibodies to fight infections. Misfolded antibodies are unavoidable byproducts in the ER upon massive production of antibodies, and they were believed to activate the XBP-1 transcription factor, which was arguably one of the most important factors in correcting protein misfolding problems and expanding the size of the ER. Thus, we chose XBP-1 to peek into the biology of the ER. Our initial pursuit of the function of XBP-1 led to surprising conclusions that XBP-1 is not activated by misfolded antibodies and XBP-1 plays minimal role in correcting misfolded proteins in B cells. These conclusions were reached by disabling B cells of their capability in making antibodies and by deleting the XBP-1 gene from the B cells. Our further investigation suggested that XBP-1 is activated by differentiation cues. Most excitingly, our work revealed new roles for XBP-1 in regulating signal transduction through the B cell receptor; in regulating the expression of important transcription factors in B cells; in maintaining proper lipid synthesis and protein glycosylation in B cells; and in colonization of stimulated B cells into the bone marrow for sustention of antibody production.

Inspired by XBP-1’s roles in maintaining a homeostatic ER, we began to examine the role of XBP-1 in B-cell leukemia whose progression does not require dramatic ER expansion like that in multiple myeloma. We chose to use the TCL1 mouse model to study B-cell leukemia because ~90% of human chronic lymphocytic leukemia (CLL) patients express the TCL1 protein, and the overexpression of TCL1 in B cells leads to the development of CLL in mice. We showed that TCL1 oncoprotein associates with XBP-1 and turns on vital ER proteins to support leukemic growth. When the function of XBP-1 is genetically deleted in TCL1 mice, significantly slower leukemic progression is observed. We further developed inhibitors to target the expression of XBP-1 and established that blocking the expression of XBP-1 by specific small-molecule chemical inhibitors can stall malignant progression of leukemia in mice and induce apoptosis in primary human leukemic cells. Currently, my laboratory continues to analyze the functions of ER proteins in malignant progression of leukemia using novel mouse models, in which we selectively deleted genes that encode critical ER-resident proteins that support the growth and survival of leukemia. We are also generating new mouse models to expand the breadth of our investigation. Our ultimate goal is to contribute to the design of effective therapeutic approaches that target dysregulated ER functions for patients with leukemia and other malignancies.

Specific laboratory projects:
(1) Investigate IRE-1-interacting proteins to further understand how targeting the IRE-1/XBP-1 pathway can lead to stalled progression of CLL.
(2) Investigate the roles of protein antigen and Toll-like receptor ligands in activating the ER stress response to promote leukemic progression.
(3) Investigate the roles of protein misfolding in B-cell leukemia.

Laboratory Personnel:
Anthony Tang, M.D., Ph.D., Staff Scientist
Andong Shao, Ph.D., Postdoctoral Fellow
Avery Lee, 2nd year PENN CAMB/CB Predoctoral Student
Qin Xu, M.S., Research Assistant
Claire Phoumyvong, PENN Master's Student
Christina Miranda, PENN Undergraduate Student
Walker Spalek, PENN Undergraduate Student

Selected Publications

Betts BC, Locke FL, Sagatys EM, Pidala J, Walton K, Menges M, Reff J, Saha A, Djeu JY, Kiluk JV, Lee MC, Kim J, Kang CW, Tang CHA, Frieling J, Lynch CC, List A, Rodriguez PC, Blazar BR, Conejo-Garcia JR, Del Valle JR, Hu CCA, and Anasetti C.: Inhibition of human dendritic cell ER stress response reduces T cell alloreactivity yet spares donor anti-tumor immunity. Front. Immunol. In press, 2018.

Bagashev A, Sotillo E, Tang CHA, Black KL, Perazzelli J, Seeholzer SH, Argon Y, Barrett DM, Grupp SA, Hu CCA, and Thomas-Tikhonenko A.: CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol. Cell Biol. 38(21): e00383-18, November 2018.

Tang CHA, Chang S, Hashimoto A, Chen YJ, Kang CW, Mato AR, Del Valle JR, Gabrilovich DI, and Hu CCA.: Secretory IgM exacerbates tumor progression by inducing accumulations of MDSCs in mice. Cancer Immunol. Res. 6(6): 696-710, June 2018.

Tang CHA, Chang S, Paton AW, Paton JC, Gabrilovich DI, Ploegh HL, Del Valle JR, and Hu CCA.: Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization. J. Cell Biol. 217(5): 1739-1755, May 2018.

Xie H, Tang CHA, Song JH, Mancuso A, Del Valle JR, Cao J, Xiang Y, Dang CV, Lan R, Sanchez DJ, Keith B, Hu CCA, and Simon MC.: IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J. Clin. Invest. 128(4): 1300-1316, April 2018.

Schutt SD, Wu YX, Tang CHA, Bastian DA, Nguyen H, Sofi MH, Zhang MM, Liu C, Helke K, Wilson C, Schnapp LM, Del Valle JR, Hu CCA, and Yu XZ.: Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice. Blood Advances 2(4): 414-427, February 2018.

Tang CHA, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, and Hu CCA.: Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 76(8): 2137-2152, April 2016.

Tang CHA, Ranatunga S, Kriss CL, Cubitt CL, Tao J, Pinilla-Ibarz JA, Del Valle JR, and Hu CCA: Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J. Clin. Invest. 124(6): 2585-2598, Jun 2014 Notes: Highlighted in Cancer Discovery. July, 2014; 4(7): OF14. (doi: 10.1158/2159-8290.CD-RW2014-114); Highlighted in Science—Business eXchange (SciBX). Jun. 19, 2014; 7(24): 12. (doi: 10.1038/scibx.2014.702).

Ranatunga S, Tang CHA, Kang CW, Kriss CL, Kloppenburg BJ, Hu CCA, and Del Valle JR.: Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity. J. Med. Chem. 57(10): 4289-301, May 2014 Notes: Highlighted in Science—Business eXchange (SciBX). Jun. 19, 2014; 7(24): 12. (doi: 10.1038/scibx.2014.702)

Kriss CL, Pinilla-Ibarz JA, Mailloux AW, Powers JJ, Tang CHA, Kang CW, Zanesi N, Epling-Burnette PK, Sotomayor EM, Croce CM, Del Valle JR, and Hu CCA: Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 120(5): 1027-38, Aug 2012.

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Last updated: 11/26/2018
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