Jialiang Wang, Ph.D.
Assistant Professor of Cancer Biology
Assistant Professor of Neurological Surgery
Director, Neurosurgical Oncology Laboratory
Nashville, TN 37232-2380
Cancer is a remarkably heterogeneous disease at all aspects. This complexity represents one of the major challenges to develop precise diagnoses and effective treatments. As such, we work toward a better understanding of cancer heterogeneity and subsequently better therapeutic approaches.
1. Cancer Stem Cells.
Over the past decade, cancer cell subpopulations with stem cell-like characteristics are identified in a wide range of human cancers, including glioma. These cells are named cancer stem cells or cancer initiating cells. Cancer stem cells have extended capacity of self-renewal and can give rise to multiple lineages of differentiated progenies. Cancer stem cells in glioma and several other cancer types exhibit preferential resistance toward conventional chemoradiotherapy and targeted therapies. Therefore, these cells are blamed to produce recurrent tumors. Our laboratory has a specific interest in the mechanisms that mediate resistance to radiation and other therapeutics in glioma stem cells. To this end, we are currently working on the Notch signaling pathway and other targets to develop glioma stem cell-targeted strategies.
2. Personalized Medicine.
The oncogene addiction model describes the dependence of certain cancers on the products of one or a few oncogenes. This model represents the paradigmatic and most successful rationale for targeted cancer therapy, which has led to remarkable clinical success in some molecularly defined subsets of cancers, such as BCR-ABL-driven chronic myelogenous leukemia, EGFR-mutated non-small cell lung cancer, and so on. With rapidly evolving new technology, the Cancer Genome Atlas (TCGA) project and other studies have greatly improved our understanding of the genetic landscape of human cancers. Through multi-institutional collaborations, we have collected a large panel of patient-derived glioblastoma samples. We are working with other groups to characterize the genome and epigenome of these samples. On the basis of this platform, we are now working to identify novel links between tumor genotypes and phenotypes with a goal to develop molecular-guided treatments.
3. Epigenetic therapy.
Our genetic information is packed in chromatins. Epigenetics include all chromatin-based events that are essential for translating genetic information into cellular functions. It has become increasingly recognized that epigenetic abnormalities are critically implicated in cancer initiation and progression. Recurrent mutations altering epigenetic regulation are increasingly identified in human cancers, including glioblastoma (e.g. IDH1/2, histone H3). Strikingly, the most recent TCGA study shows that nearly half of glioblastoma tumors carry at least one mutation that affects an epigenetic regulator. We recently identified crucial functions of the BET family bromodomain proteins in proliferation and survival of glioblastoma with diverse genetic profiles. The BET proteins are epigenetic readers that specifically bind to acetylated histones and direct active transcription. Inhibition of BET proteins by small molecular inhibitors or shRNA shows that BET proteins are implicated in transcription of many important oncogenes. As such, targeting BET bromodomain proteins is expected to generate broad anti-neoplastic effects in glioblastoma and many other cancer types. On the basis of these findings, we want to develop more effective combinations that can improve FDA-approved drugs or drugs currently in pipeline. We are also interrogating the role of BET bromodomain proteins in other cancer types based on some key targets genes that we have identified.
- Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J. InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma. Clin. Cancer Res [print-electronic]. 2016 Apr 4/1/2016; 22(7): 1767-76. PMID: 26561558, PMCID: PMC4818693, PII: 1078-0432.CCR-15-1677, DOI: 10.1158/1078-0432.CCR-15-1677, ISSN: 1078-0432.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/26561558.
- Ma Y, Gong Y, Cheng Z, Loganathan S, Kao C, Sarkaria JN, Abel TY, Wang J. Critical functions of RhoB in support of glioblastoma tumorigenesis. 2015;
Available from: http://www.ncbi.nlm.nih.gov/pubmed/25216671.
- Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J. Insulin-mediated signaling promotes proliferation and survival of glioblastoma through AKT activation. 2015;
Available from: http://www.ncbi.nlm.nih.gov/pubmed/26136493.
- Cheng Z, Gong Y, Ma Y, Lu K, Lu X, Pierce LA, Thompson RC, Muller S, Knapp S, Wang J. Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res [print-electronic]. 2013 Apr 4/1/2013; 19(7): 1748-59. PMID: 23403638, PMCID: PMC4172367, PII: 1078-0432.CCR-12-3066, DOI: 10.1158/1078-0432.CCR-12-3066, ISSN: 1078-0432.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/23403638.
- Wang J, Sullenger BA, Rich JN. Notch signaling in cancer stem cells. Adv. Exp. Med. Biol. 2012; 727: 174-85. PMID: 22399347, DOI: 10.1007/978-1-4614-0899-4_13, ISSN: 0065-2598.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/22399347.
- Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB, Rich JN. Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell. 2010 May 5/7/2010; 6(5): 421-32. PMID: 20452317, PMCID: PMC2884275, PII: S1934-5909(10)00113-X, DOI: 10.1016/j.stem.2010.02.018, ISSN: 1875-9777.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/20452317.
- Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, Rich JN, Sullenger BA. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010 Jan; 28(1): 17-28. PMID: 19921751, PMCID: PMC2825687, DOI: 10.1002/stem.261, ISSN: 1549-4918.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/19921751.
- Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN. Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells. 2009 Oct; 27(10): 2393-404. PMID: 19658188, PMCID: PMC2825688, DOI: 10.1002/stem.188, ISSN: 1549-4918.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/19658188.
- Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, Hjelmeland AB, Rich JN. C-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE [print-electronic]. 2008; 3(11): e3769. PMID: 19020659, PMCID: PMC2582454, DOI: 10.1371/journal.pone.0003769, ISSN: 1932-6203.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/19020659.
- Wang J, An H, Mayo MW, Baldwin AS, Yarbrough WG. LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB. Cancer Cell. 2007 Sep; 12(3): 239-51. PMID: 17785205, PII: S1535-6108(07)00201-2, DOI: 10.1016/j.ccr.2007.07.002, ISSN: 1535-6108.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/17785205.
- Wang J, He X, Luo Y, Yarbrough WG. A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. Biochem. J. 2006 Jan 1/15/2006; 393(Pt 2): 489-501. PMID: 16173922, PMCID: PMC1360699, PII: BJ20050960, DOI: 10.1042/BJ20050960, ISSN: 1470-8728.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/16173922.