The long-term goal of our laboratory is to illuminate the function of immune surface molecules and to open up a new research field at the interface of cancer, immunology, and stem cell research. We are also actively developing novel therapies for cancer treatment.
1) The function of ITIM receptors in cancer and hematopoietic stem cells. The leukocyte Ig-like receptor subfamily B (LILRB) is a group of type I transmembrane glycoproteins with extracellular Ig-like domains and intracellular ITIMs (immunoreceptor tyrosine-based inhibitory motifs). This group of receptors contains five members, LILRB1 to LILRB5. LILRB 1-5 transduce signals via ITIMs that recruit phosphatase SHP-1, SHP-2, or SHIP, leading to negative regulation of immune cell activation. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by tumors. We cloned LILRB2 as a receptor for the “orphan ligand” Angptl2, revealing unexpected function of classical immune inhibitory receptors in maintenance of stemness of hematopoeitic stem cells (HSCs). Subsequently we demonstrated that several members of LILRB family are expressed by tumor cells, including certain hematopoietic and solid cancer cells, and may directly regulate cancer development and relapse as well as the activity of cancer stem cells. We further elucidated unique signaling downstream of a representative ITIM-containing receptor in leukemia cells. LILRBs thus have dual concordant roles in tumor biology – as immune checkpoint molecules and as tumor-sustaining factors. Importantly, the study of knockout mice indicated that LILRBs do not affect hematopoiesis and normal development. Therefore LILRBs may represent ideal targets for tumor treatment. Targeting LILRBs may perfectly combine immunotherapy and targeted therapy, and lead to the development of novel therapies for cancer treatment.
2) Angiopoietin-like proteins and receptors. In addition to LILRB2, we are identifying additional receptors for various angiopoietin-like proteins. We are studying the function of these ligands and receptors in cancer, stem cells, and immunity.
3) The role of PD-L1 in hematopoietic stem cells (HSCs). We demonstrated that the immune privilege of HSCs can be regulated by controlling surface expression of the immune inhibitor PD-L1, and ex vivo expanded HSCs efficiently overcome MHC barrier and engraft allogeneic recipient mice.
4) The opposite effects of fasting on different types of cancer. How dietary restrictions affect hematopoietic malignancies are unknown. We showed that fasting alone robustly inhibits initiation and reverses later development of acute lymphoblastic leukemia (both B-ALL and T-ALL) but not acute myeloid leukemia (AML). Fasting blocks ALL development by upregulation of leptin receptor (LepR) and its downstream signaling through Prdm1. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and suggest new avenues for development of novel strategies for leukemia treatment.
Awards and honors
- Basil O'Connor Scholar
- American Society of Hematology Junior Faculty Scholar
- New Investigator Award, American Cancer Society/UT Southwestern
- Michael L. Rosenberg Scholar in Biomedical Research, UT Southwestern
- Howard Temin KO1 award, National Cancer Institute
- Gabrielle’s Angel Foundation for Cancer Research Fellow
- Royan International Research Award
- Leukemia & Lymphoma Society Scholar Award
- Hortense L. and Morton H. Sanger Professorship in Oncology
Selected Publications (of a total of 88)
- Zhang CC, Krieg S, and Shapiro DJ. 1999. HMG-1 Stimulates Estrogen Response Element Binding by Estrogen Receptor from Stably Expressed HeLa Cells. Molecular Endocrinology 13: 632-643.
- Zhang CC and Shapiro DJ. 2000. Activation of the p38 Mitogen-activated Protein Kinase Pathway by Estrogen or by 4-Hydroxy Tamoxifen is Coupled to Estrogen Receptor-induced Apoptosis. Journal of Biological Chemistry 275: 479-486.
- Zhang CC, Glenn K, Kuntz M, and Shapiro DJ. 2000. High Level Expression of Full-length Estrogen Receptor in E. coli is Facilitated by the Uncoupler of Oxidative Phosphorylation, CCCP. Journal of Steroid Biochemistry and Molecular Biology 74: 169-178.
- Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB. 2002. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 99: 16309-16313.
- Zhang CC and Lodish HF. 2004. Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103: 2513-2521.
- Zhang CC and Lodish HF. 2005. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105: 4314-4320.
- Thomas M, Lu JJ, Ge Q, Zhang CC, Chen J, Klibanov AM. 2005. Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc Natl Acad Sci U S A 102: 5679-5684.
- Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, Lodish HF. 2006. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine 12: 240-245.
- Zhang CC, Steele AD, Lindquist S, Lodish HF. 2006. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A 103: 2184-2189.
- Liao MJ*, Zhang CC*, Zhou B*, Zimonjic DB, Mani SA, Kaba M, Gifford A, Reinhardt F, Popescu NC, Guo W, Eaton EG, Lodish HF, Weinberg RA. 2007. Enrichment of a population of mammary gland cells that forms mammospheres and has in vivo repopulating activity. Cancer Res. 67: 8131-8138 (* first authors).
- Zhang CC*, Kaba M, Iizuks S, Huynh H, Lodish HF*. 2008. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells. Blood 111: 3415-3423 (* corresponding authors)
- Zhang CC and Lodish HF. 2008. Cytokines regulation of hematopoietic stem cell functions. Current Opinion in Hematology 15: 307-311.
- Huynh H, Iizuka S, Kaba M, Kirak O, Zheng J, Lodish HF, Zhang CC. 2008. IGFBP2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells 26: 1628-1635.
- Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704-715.
- Patrick DM, Zhang CC, Tao Y, Yao H, Qi X, Schwarz RJ, Huang LJ, Olson EN. 2010. Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3z. Genes and Development 24:1614-1619.
- Simsek T, Kocabas F, Zheng J, DeBerardinis RJ, Olson EN, Schneider JW, Zhang CC*, Sadek HA*. 2010. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380-390. (* corresponding authors)
- Zheng J, Huynh H, Umikawa M, Silvany R, Zhang CC. 2011. Angiopoietin-like protein 3 supports the activity of mouse hematopoietic stem cells in the bone marrow niche. Blood 117:470-479
- Zheng J, Umikawa M, Zhang S, Huynh H, Silvany R, Chen BPC, Chen L, Zhang CC. 2011. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9:119-130
- Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, Holzenberger M, Zhang W, Zhang CC. 2011. IGF Binding Protein 2 Supports the Survival and Cycling of Hematopoietic Stem Cells. Blood 118:3236-3243
- Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Kang X, Silvany R, Wan X, Ye J, Canto AP, Chen SH, Wang HY, Ward ES, Zhang CC. 2012. Inhibitory receptors bind Angptls and support blood stem cells and leukemia development. Nature 485:656-660
- Kocabas F, Zheng J, Thet S, Copeland NG, Jenkins NA, DeBerardinis RJ, Zhang CC*, Sadek HA*. 2012. Meis1 regulates the metabolic phenotype and oxidative defense of hematopoietic stem cells. Blood. 120(25):4963-72 (*corresponding authors)
- Zhang CC, Sadek H. 2014. Hypoxia and Metabolic Properties of Hematopoietic Stem Cells. Antioxidants & Redox Signaling. 20(12):1891-1901
- Zheng J, Lu Z, Kocabas F, Bottcher RT, Costell M, Kang X, Liu X, DeBerardinis RJ, Wang Q, Chen G, Sadek H, Zhang CC. 2014. Profilin-1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow. Blood. 123: 992-1001
- Zhang CC. 2014. Novel signaling axis in CML-initiating cells. Blood. 123: 2443-2445
- Deng M*, Lu Z*, Zheng J, Wan X, Chen X, Hirayasu K, Sun H, Lam Y, Chen L, Wang Q, Song C, Huang N, Gao GF, Jiang Y, Arase H, Zhang CC. 2014. A motif in LILRB2 critical for Angptl2 binding and activation. Blood. 124(6):924-35
- Yu X, Wang Y, Deng M, Li Y, Ruhn KA, Zhang CC, Hooper LV. 2014. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. eLife. 10.7554/eLife.04406
- Kocabas F, Zheng J, Zhang CC, Sadek HA. 2014. Metabolic characterization of hematopoietic stem cells. Methods in Molecular Biology. 1185:155-164.
- Kang X, Cui C, Lu Z, Dong B, Han X, Tyner JW, Coligan JE, Collins R, You JM, Zhang CC. 2015. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukemia development. Nature Cell Biology. 17(5):665-677
- Lin MI, Price EN, Boatman S, Hagedorn EJ, Trompouki E, Satishchandran S, Carspecken CW, Uong A, DiBiase A, Yang S, Canver MC, Dahlberg A, Lu Z, Zhang CC, Orkin SH, Bernstein ID, Aster JC, White RM, Zon LI. 2015 Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling. eLife. 10.7554/eLife.05544
- Kimura W, Xiao F, Canseco DC, Muralidhar S, Thet S, Zhang HM, Abderrahman Y, Chen R, Garcia JA, Shelton JM, Richardson JA, Ashour AM, Asaithamby A, Liang H, Xing C, Lu Z, Zhang CC, Sadek HA. 2015. Hypoxia fate-mapping identifies cycling cardiomyocytes in the adult heart. Nature. 523(7559):226-23
- Kang X, Kim J, Deng M, John S, Chen H, Wu G, Phan H, Zhang CC. 2016. Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors. Cell Cycle. 15(1):25-40
- Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah A, Zhang H, Faber JE, Kinter MT, Szweda LI, Xing C, Deberardinis R, Oz O, Lu Z, Zhang CC, Kimura W, Sadek HA. 2017. Hypoxia induces heart regeneration in adult mice. Nature. 541(7636):222-227
- Lu Z, Xie J, Wu G, Shen J, Collins R, Chen W, Kang X, Luo M, Zou Y, Huang LJ, Amatruda JF, Slone T, Winick N, Scherer PE, Zhang CC. 2017. Fasting selectively blocks acute lymphoblastic leukemia development via leptin receptor upregulation. Nature Medicine. 23(1):79-90
John S, Chen H, Deng M, Gui X, Wu G, Chen W, Li Z, Zhang N, An Z, Zhang CC. 2018. A novel anti-LILRB4 CAR-T cell for the treatment of monocytic AML. Molecular Therapy. 26(10):2487-2495
Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, He L, Chen Y, Chen H, Luo W, Lu Z, Xie J, Churchill H, Xu Y, Zhou Z, Wu G, Yu C, John S, Hirayasu K, Nguyen N, Liu X, Huang F, Li L, Deng H, Tang H, Sadek AH, Zhang L, Huang T, Zou Y, Chen B, Zhu H, Arase H, Xia N, Jiang Y, Collins R, You MJ, Homsi J, Unni N, Lewis C, Chen GQ, Fu YX, Liao XC, An Z, Zheng J, Zhang N, Zhang CC.2018. LILRB4 signaling in leukemia cells mediatesT cell suppression and tumor infiltration. Nature. https://doi.org/10.1038/s41586-018-0615-z