- PhD, University of Indiana
- Associate Professor, Microbiology, Immunology, and Cancer Biology
Mouse models of brain cancers
Use MADM, a mouse genetic mosaic model, to study how tumor cells attack
To treat cancer effectively, great efforts have been devoted to molecularly targeted therapy. While there have been great examples of success, cancer cells often develop drug resistance to evade therapy. To increase the efficacy of cancer therapy, our lab uses a genetic mosaic mouse model termed MADM to study how tumor cells attack in vivo from the tumor-initiating stage and at the single-cell resolution.
The first important cellular level question is the cell of origin for cancer. Since each cell types in our body have their unique "personality"/signaling context, they often respond to the same genetic mutations in entirely different fashion. Using a MADM glioma model, we have successfully identified oligodendrocyte precursor cells (OPCs) as the cell of origin, while other brain cell types fail to transform by the same set of mutations. We are currently investigate the unique sensitivity of OPCs and hope to develop novel treatment strategy by removing the transforming responsiveness in OPCs.
The second important cellular mechanism is the relationship between tumor and their sibling normal cells. Through careful analysis, we found that mutant OPCs massively outcompete WT OPCs months before the onset of malignancy. Such competitiveness predicts that all cytotoxic treatment will select for the most malignant tumor cells and cause rapid relapse even with initial tumor shrinkage. This is devastating news and prompts us to look into novel strategies for glioma treatment. Using genetic tricks, we introduced competitive yet non-transforming cells to remove the competitive edge of mutant OPCs, which completely prevented glioma formation. In the future, we plan to follow up this exciting finding to screen for compounds that can block the competition of tumor OPCs as a novel strategy to control the progression of glioma.
Lastly, tumor cells are never alone, and their interactions with niche cells play critical roles for tumor initiation and progression. Using the MADM model for medulloblastoma, we found that tumor cells can trans-differentiate into a distinct cell type, suggesting that tumor could build its own niche. More interestingly, we found that tumor cells rely on these trans-differentiated cells to maintain proliferative capacity and prevent differentiation and apoptosis. Currently we are looking into the molecular crosstalk between tumor and niche cells, in hope to develop a method to cut off the external support toward tumor cells for the treatment of medulloblastoma.
In summary, our findings clearly demonstrate that we must precisely analyze both molecular and cellular mechanisms of cancer in order to devise effective therapeutic strategies.
- He H, Yao M, Zhang W, Tao B, Liu F, Li S, Dong Y, Zhang C, Meng Y, Li Y, Hu G, Luo C, Zong H, Lu Y. MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment. Cellular & molecular immunology. 2015. PMID: 26189368
- Zong H, Parada L, Baker S. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harbor perspectives in biology. 2015;7(5). PMID: 25635044
- Galvao R, Kasina A, McNeill R, Harbin J, Foreman O, Verhaak R, Nishiyama A, Miller C, Zong H. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(40): E4214-23. PMID: 25246577 | PMCID: PMC4210043
- Galvão R, Zong H. Inflammation and Gliomagenesis: Bi-Directional Communication at Early and Late Stages of Tumor Progression. Current pathobiology reports. 2013;1(1): 19-28. PMID: 23538742 | PMCID: PMC3607461
- Gay L, Miller M, Ventura P, Devasthali V, Vue Z, Thompson H, Temple S, Zong H, Cleary M, Stankunas K, Doe C. Mouse TU tagging: a chemical/genetic intersectional method for purifying cell type-specific nascent RNA. Genes & development. 2013;27(1): 98-115. PMID: 23307870 | PMCID: PMC3553287
- Henner A, Ventura P, Jiang Y, Zong H. MADM-ML, a mouse genetic mosaic system with increased clonal efficiency. PloS one. 2013;8(10): e77672. PMID: 24143253 | PMCID: PMC3797059
- Packard A, Georgas K, Michos O, Riccio P, Cebrian C, Combes A, Ju A, Ferrer-Vaquer A, Hadjantonakis A, Zong H, Little M, Costantini F. Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud. Developmental cell. 2013;27(3): 319-30. PMID: 24183650 | PMCID: PMC3926506
- Liu C, Zong H. Developmental origins of brain tumors. Current opinion in neurobiology. 2012;22(5): 844-9. PMID: 22560511 | PMCID: PMC3432164
- Tasic B, Miyamichi K, Hippenmeyer S, Dani V, Zeng H, Joo W, Zong H, Chen-Tsai Y, Luo L. Extensions of MADM (mosaic analysis with double markers) in mice. PloS one. 2012;7(3): e33332. PMID: 22479386 | PMCID: PMC3314016
- Zong H, Verhaak R, Canolk P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert review of molecular diagnostics. 2012;12(4): 383-94. PMID: 22616703 | PMCID: PMC3368274
- Foo L, Allen N, Bushong E, Ventura P, Chung W, Zhou L, Cahoy J, Daneman R, Zong H, Ellisman M, Barres B. Development of a method for the purification and culture of rodent astrocytes. Neuron. 2011;71(5): 799-811. PMID: 21903074 | PMCID: PMC3172573
- Liu C, Sage J, Miller M, Verhaak R, Hippenmeyer S, Vogel H, Foreman O, Bronson R, Nishiyama A, Luo L, Zong H. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell. 2011;146(2): 209-21. PMID: 21737130 | PMCID: PMC3143261
- Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas J, Gill R, Huillard E, Liu C, Zong H, Rowitch D, Barres B, Verma I, Kosik K. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene. 2011;31(15): 1884-95. PMID: 21874051 | PMCID: PMC4160048
- Tasic B, Hippenmeyer S, Wang C, Gamboa M, Zong H, Chen-Tsai Y, Luo L. Site-specific integrase-mediated transgenesis in mice via pronuclear injection. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(19): 7902-7. PMID: 21464299 | PMCID: PMC3093482
- Hippenmeyer S, Youn Y, Moon H, Miyamichi K, Zong H, Wynshaw-Boris A, Luo L. Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration. Neuron. 2010;68(4): 695-709. PMID: 21092859 | PMCID: PMC3044607
- Muzumdar M, Luo L, Zong H. Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM). Proceedings of the National Academy of Sciences of the United States of America. 2007;104(11): 4495-500. PMID: 17360552 | PMCID: PMC1810340
- Zong H, Espinosa J, Su H, Muzumdar M, Luo L. Mosaic analysis with double markers in mice. Cell. 2005;121(3): 479-92. PMID: 15882628