The long-term goal of our laboratory is to gain a comprehensive understanding of the molecular mechanisms that govern the adult stem cell fate determination, and to apply the knowledge obtained from these studies to the development of new stem cell transplantation strategies and gene therapies for treating cancer and other diseases. Our study is focused on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs).
We are studying the roles of immune inhibitory receptors in stem cells and cancer. Recently we identified the human leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) and mouse paired Ig-like receptor (PirB) as receptors for angiopoietin-like proteins. These receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their intracellular domains and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP. Our continuing research has indicated that these and some other ITIM-containing inhibitory receptors support the self-renewal and survival of HSCs and acute myeloid leukemia stem cells. In particular, our results suggest that, some leukemia stem cells express high levels of ITIM-inhibitory receptors. The current treatment options including chemotherapy may not efficiently target these cancer stem cells, because these inhibitory receptors enable the leukemia stem cells to survive the conventional therapies eventually resulting in tumor relapse. Therefore, the blockade of inhibitory receptor signaling may prove to be a novel strategy to eliminate leukemia stem cells and lead to complete remission of patients.
We seek to study:
- Ex vivo expansion of HSCs for cell therapy and gene therapy.
- Cloning the receptors for Angiopoietin-like proteins, and the function and signaling of the receptors in stem cells and cancer.
- Roles of ITIM-receptors in cancer and stem cells.
- Interplay among immune surface molecules, stem cells, and cancer.
Our novel finding will contribute to the opening up of a new research area to study the roles of ITIM-receptors in stem cells and cancer development, and also likely lead to the development of novel strategies for stem cell-based therapy and cancer 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
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Zhang CC and Lodish HF. 2005. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105: 4314-4320.
7. 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.
8. 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.
9. 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.
10. Thomas M, Lu JJ, Zhang CC, Chen J, Klibanov AM. 2007. Identification of Novel Superior Polycationic Vectors for Gene Delivery by High-throughput Synthesis and Screening of a Combinatorial Library. Pharm Res 24: 1564-1571.
11. 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).
12. 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)
13. Zhang CC and Lodish HF. 2008. Cytokines regulation of hematopoietic stem cell functions. Current Opinion in Hematology 15: 307-311.
14. 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.
15. 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.
16. Zhao L, Dong H, Zhang CC, Kinch L, Osawa M, Iacovino M, Grishin NV, Kyba M, Huang L. 2009. A JAK2 inter-domain linker relays Epo receptor engagement signals to kinase activation. Journal of Biological Chemistry 284:26988-26998.
17. Huynh H, Kaba M, Rudra S, Zheng J, Wu CJ, Lodish HF, Zhang CC. 2009. IGFBP2 supports ex vivo expansion of hematopoietic stem cells. IGFs: Local Repair and Survival Factors Throughout Life Span. D.R. Clemmons, I. Robinson, and Y. Christen, editors. Springer. 21-42.
18. Lou Z, Zhang CC, Tirado CA, Slone T, Zheng J, Zaremba CM, Oliver D, Chen W. 2010. infantile mixed phenotype acute leukemia (bilineal and biphenotypic) with t(10;11)(p12;q23);MLL-MLLT10. Leukemia Research 34:1107-1109.
19. 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.
20. 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)
21. 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
22. Zhang S, Yajima H, Huynh H, Zheng J, Callen E, Chen H, Wong N, Bunting S, Lin Y, Lee K, Story M, Gapud E, Sleckman BP, Nussenzweig A, Zhang CC, Chen DJ, Chen BPC. 2011. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in multiple DNA repair pathways. Journal of Cell Biology 193:295-305
23. Huynh H, Zheng J, Umikawa M, Silvany R, Xie XJ, Wu CJ, Holzenberger M, Wang Q, Zhang CC. 2011. Components of the hematopoietic compartments in tumor stroma and tumor-bearing mice. PLoS ONE 6:e18054
24. Zhang L, Tan C, Wang Q, Zhang CC. 2011. Anion/Cation Induced Optical Switches Based on Luminescent Lanthanide (Tb3+ and Eu3+) Hydrogels. Photochemistry and Photobiology 87:1036-1041
25. Tan C, Wang Q, Zhang CC. 2011. Optical and Electrochemical Responses of an Anthrax Biomarker Based on Single-Walled Carbon Nanotubes Covalently Loaded with Terbium Complexes. Chemical Communications 47:12521–12523
26. Zheng Y, Tan C, Wang Q, Zhang CC. 2011. 2-(3-Pyridyl)imidazole-4,5-dicarboxylic acid based lanthanide luminescent anion sensor. Solid State Sciences 13:1687e1691
27. Nair A, Shen J, Lotfi P, Ko C-Y, Zhang CC, Tang L. 2011. Biomaterial implants mediate autologous stem cell recruitment in mice. Acta Biomaterialia 7:3887-3895
28. 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
29. Schuster K, Zheng J, Arbini AA, Zhang CC, Scaglioni PP. 2011. Selective targeting of the mTOR1/2 protein kinase complex leads to antileukemic effects in vitro and in vivo. Blood Cancer Journal 1:e34
30. 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
31. Zheng J, Song C, Zhang CC. 2011. A new chapter: hematopoietic stem cells are direct players in immunity. Cell & Bioscience 1(1):33
32. 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
33. 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)
34. Umikawa M, Zhang CC. 2012. Inhibitory receptors bind Angptls and support blood stem cells and leukemia development. Experimental Medicine 30:2969-2973
35. Zhang CC. 2012. Hematopoietic stem cells: interplay with immunity. American Journal of Blood Research 2:219-227
36. Zhang CC, Sadek H. 2014. Hypoxia and Metabolic Properties of Hematopoietic Stem Cells. Antioxidants & Redox Signaling. 20(12):1891-1901
37. Li Y, Zheng Y, Wang Q, Zhang CC. 2013. Synthesis of luminescent YVO4:Eu3+ submicrometer crystals through hydrogels as directing agents. Materials Chemistry and Physics, 135:451-456.
38. Chen X, Zheng J, Zou Y, Song C, Hu X, Zhang CC. 2013. IGF Binding Protein 2 is a Cell-autonomous Factor Supporting Survival and Migration of Acute Leukemia Cells. Journal of Hematology & Oncology. 6:72
39. 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
40. Shen J, Nair A, Saxena R, Zhang CC, Borrelli J, Tang L. 2014. Tissue Engineering Bone Using Autologous Progenitor Cells in the Peritoneum. PlosOne. 9(3): e93514
41. Zhang CC. 2014. Novel signaling axis in CML-initiating cells. Blood. 123: 2443-2445
42. 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. E-published on June 4