Chih-Chi Andrew Hu, PhD
Wistar Institute Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine
Contact InformationTranslational Tumor Immunology, Wistar Institute, 3601 Spruce Street
Philadelphia, PA, 19104-4265
The biology of the endoplasmic reticulum in health and disease
Endoplasmic reticulum (ER); B cell; protein folding and assembly; glycosylation; membrane protein trafficking
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.
Anthony Tang, M.D., Ph.D., Postdoctoral Fellow
Joseph Zundell, B.S., Research Assistant
Joseph Balowski, B.S., Research Assistant
Shiun Chang, M.S., Research Assistant
MS (Cancer Biology), National Sun Yat-Sen University, Taiwan, 1999
MS (Pharmacology), New York University School of Medicine, 2004
PhD (Pharmacology), New York University School of Medicine, 2006
Post-doctoral Fellow, Whitehead Institute for Biomedical Research, Cambridge, MA, 2006-2010
Awards and Honors
Honorary Member of the Phi Tau Phi Scholastic Honor Society, 1999-1999
Presidential Travel Award, National Sun Yat-Sen University, 1999-1999
Young Investigator Travel Award, The Society for Basic Urologic Research, 2004-2004
WIPDA Education Award, Whitehead Institute for Biomedical Research, 2009-2009
Whitehead Appreciation Award, Whitehead Institute for Biomedical Research, 2010-2010
Miles for Moffitt Award, Florida Bank, 2011-2011
Hollis Brownstein Research Grant, Leukemia Research Foundation, 2012-2012
American Cancer Society Institutional Research Grant, 2012-2012
Memberships and Professional Organizations
American Association for Cancer Research, 1999 - 2003
American Society for Cell Biology, 2009 - Present
The European Association for Cancer Research, 2014 - Present
Agonist-mediated activation of STING induces apoptosis in malignant B cells.
Tang CHA, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, and Hu CCA., Cancer Res. In press(): , 2016
Site-specific proteolysis mobilizes Torsin A from the membrane of the endoplasmic reticulum in response to ER stress and B cell stimulation.
Zhao C, Brown RSH, Tang CHA, Hu CCA, and Schlieker C., J. Biol. Chem. In press(): , 2016
Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival.
Tang CHA, Ranatunga S, Kriss CL, Cubitt CL, Tao J, Pinilla-Ibarz JA, Del Valle JR, and Hu CCA, J. Clin. Invest. 124(6): 2585-2598, 2014
Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity.
Ranatunga S, Tang CHA, Kang CW, Kriss CL, Kloppenburg BJ, Hu CCA, and Del Valle JR., J. Med. Chem. 57(10): 4289-301, 2014
Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice.
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, Blood 120(5): 1027-38, 2012
IgG1+ ovalbumin-specific B cell transnuclear mice show class switch recombination in rare allelically-included B cells.
Dougan SK, Ogata S, Hu CCA, Grotenbreg GM, Guillen E, Jaenisch R, and Ploegh HL, Proc. Natl. Acad. Sci. USA. 109(34): 13739-44, 2012
Derlin-2 deficient mouse reveals an essential role for protein dislocation in chondrocytes.
Dougan SK, Hu CCA, Paquet ME, Greenblatt MB, Kim J, Lilley BN, Watson N, and Ploegh HL., Mol. Cell Biol. 31(6): 1145-59, 2011
Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes.
Hu CCA, Dougan SK, Virreira-Winter S, Paton AW, Paton, JC, and Ploegh HL, J. Exp. Med. 206(11): 2429-2440, 2009
XBP-1-deficient plasmablasts show normal protein folding but altered glycosylation and lipid synthesis.
McGehee AM, Dougan SK, Klemm EJ, Shui G, Park B, Kim YM, Watson N, Wenk MR, Ploegh HL, and Hu CCA, J. Immunol. 183(6): 3690-3699, 2009
XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells.
Hu CCA, Dougan SK, McGehee AM, Love JC, and Ploegh HL, EMBO J. 28(11): 1624-1636, 2009