The main focus of the Cancer and Stem Cell Laboratory is to study how normal stem cells are transformed into cancer stem cells and to develop effective new therapies that specifically target and destroy cancer stem cells. These cells, which are often resistant to chemotherapy, are now believed to be the engine driving the growth of cancer and the root cause of treatment resistance and relapse.

• Cancer biology
• Stem cell biology
• Molecular and cell biology
• Targeted therapies (incl. RNA therapeutics and CAR T-cell therapy)
• Nanoparticle-based drug delivery
• Cellular barcoding
• Signaling pathways
• Cancer metabolism
• Functional genomics and epigenomics
• Single-cell multiomics and single-cell CUT&Tag

There are multiple PhD/Master/Honours student projects available in the Cancer and Stem Cell Laboratory. Several of them have been described in the Project Opportunities.

Project Opportunities - PhD, Masters and Honours students

• Targeting leukemia stem cells: the path towards a cure for therapy-resistant cancer

Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer with a 5-year survival rate of only 27.4% in Australia. Despite intensive chemotherapy, the majority of patients with AML relapse and ultimately die from their disease. Clinical evidence has supported the important role of leukemia stem cells in the high relapse rate of AML patients. Leukemia stem cells reside in a mostly quiescent state and as such they are resistant to chemotherapy. These cells possess several unique features such as self-renewal and escaping from cell death. Targeted elimination of leukemia stem cells is now believed to be essential for AML patients to achieve a complete remission. Our studies have identified key self-renewal pathways (Science 2010; Blood 2014, 2024; Leukemia 2016, 2019; Cancer Cell 2020) for stem cell formation and our exciting new findings of pathway inhibitors provide promising therapeutic opportunities to specifically target leukemia stem cells. This project is designed to understand the mechanisms of action of pathway inhibitors in order to develop effective stem cell-targeted therapies that will benefit patients suffering from treatment resistance and disease relapse.

• Epigenetic mechanisms of malignant stem cell regulation

Epigenetic regulation of gene expression plays crucial roles in stem cell functions. Inappropriate maintenance of epigenetic ‘marks’ - that sit on the nuclear DNA of cancer cells and control the activity of genes - results in activation of oncogenic self-renewal pathways leading to the formation of malignant stem cells and the subsequent development of cancer. Unlike genetic alterations, epigenetic marks can be reversed by treatments with chromatin-modifying drugs, making them suitable targets for epigenetic-based therapies. Our studies have uncovered key epigenetic regulators that contribute to cancer formation and progression. This project aims at exploring epigenetic mechanisms that govern malignant stem cell function and at discovering chromatin-modifying drugs that are capable of reversing cancer-associated epigenetic marks. The outcome of this study will have the potential to develop innovative epigenetic therapies.

• RNA-based therapeutics through the control of stem cell fate

The recent discovery of non-coding RNAs (ncRNAs) has dramatically altered our view of gene regulation in cancer. MicroRNAs (miRNAs) are a class of ncRNAs that function to regulate gene expression at the transcriptional and post-transcriptional level, playing a pivotal role in cancer progression and metastasis. Using an integrated miRNA-mRNA expression profiling analysis, we have documented a miRNA regulatory network, whose downregulation is associated with the aggressive phenotype of cancer (Haematologica 2019). This study will investigate how a crosstalk between miRNA regulatory network and epigenetic/signaling pathways determines the fate of stem cells and this will pave the way for developing novel RNA-based therapeutics in effectively destroying malignant stem cells.

• Techniques: Single cell omics analysis (transcriptomics, proteomics and epigenomics), cell-based assays, in vitro drug response assays, molecular and cell biology, gene and protein expression, immunofluorescence, gene editing, flow cytometry, patient-derived xenograft mouse models, in vivo preclinical drug testing, stem cell technologies etc.

• Significance: Successful completion of these projects will generate new insights into cancer and stem cell biology, identify novel therapeutic targets, and provide preclinical validation of therapeutic potential. These studies therefore have the potential to lead to the development of novel therapies that directly and selectively kill malignant stem cells, which are now considered to be the root cause of cancer progression, resistance to chemotherapy, and ultimate relapse.

Selected Publications

2024

• Hassan N, Yi H, Malik B, Gaspard-Boulinc L, Samaraweera SE, Casolari DA, Seneviratne J, Balachandran A, Chew T, Duly A, Carter DR, Cheung BB, Norris M, Haber M, Kavallaris M, Marshall GM, Zhang XD, Liu T, Wang J, Liebermann DA, D’Andrea RJ,Wang JY. Loss of stress sensorGADD45Apromotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.Blood. 2024. 144 (1): 84-98. (IF 21)

2023

• Mekapogu AR, Suárez CA, Wang JY. Exploring cancer stem cells signaling pathways. Frontiers in Oncology. 2023. 13:1274509. (IF 3.5)

2022

• Kim M, Singh M, Lee B, Hibbs M, Richardson K, Ellies L, Wintle L, Stuart LM, Wang JY, Voon DC, Blancafort P, Wang J, Kim J, Leedman PJ, Woo AJ. A MYC, ZNF148, ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer. Oncogenesis. 2022. 11:60. (IF 6.9)

2021

• Teng L, Feng YC, Guo ST, Wang PL, Wang SX, Zhang SN, Qi TF, La T, Zhang YY, Zhao XH, Zhang D, Wang JY, Shi Y, Li JM, Cao H, Liu T, Thorne RF, Jin L, Shao F, Zhang XD. The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis.Nature Communications. 2021. 12(1):3734. (IF 14.7)

• Chen J, Nelson C, Wong M, Tee AE, Liu PY, La T, Fletcher JI, Kamili A, Mayoh C, Bartenhagen C, Trahair TN, Xu N, Jayatilleke N, Wong-Erasmus M, Peng H, Atmadibrata B, Cheung BB, Lan Q, Bryan TM, Mestdagh P, Vandesompele J, Combaret V, Boeva V, Wang JY, Janoueix-Lerosey I, Cowley MJ, MacKenzie KL, Dolnikov A, Li J, Polly P, Marshall GM, Reddel RR, Norris MD, Haber M, Fischer M, Zhang XD, Pickett HA, and Liu T. Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy. Clinical Cancer Research. 2021. 27(5):1438-1451. (IF 10)

• Lan Q, Liu PY, Bell JL, Wang JY, Hüttelmaier S, Zhang XD, Zhang L, Liu T. The emerging roles of RNA m⁶A methylation and demethylation as critical regulators of tumorigenesis, drug sensitivity, and resistance. Cancer Research. 2021. 81(13):3431-3440. (IF 12.5)

• La T, Chen S, Guo T, Zhao XH, Teng L, Li D, Carnell M, Zhang YY, Feng YC, Cole N, Brown AC, Zhang D, Dong Q, Wang JY, Cao H, Tao Liu, Thorne RF, Shao FM, Zhang XD, Jin L. Visualization of endogenous p27 and Ki67 reveals the importance of a c-Myc-driven metabolic switch in promoting survival of quiescent cancer cells. Theranostics. 2021. 11(19): 9605-9622. (IF 12.4)

2020

• Salik B, Yi H, Hassan N, Santiappillai N, Vick B, Connerty P, Duly A, Trahair T, Woo AJ, Beck D, Liu T, Spiekermann K, Jeremias I, Wang J, Kavallaris M, Haber M, Norris MD, Liebermann DA, D'Andrea RJ, Murriel C, Wang JY. Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020. 38(2):263-278. (IF 48.8)

• Hassan N, Yang J and Wang JY. An improved protocol for establishment of AML patient-derived xenograft models. STAR Protocols. 2020. 1(3):100156.

2019

• Lynch JR, Salik B, Connerty P, Vick B, Leung H, Pijning A,Jeremias I, Spiekermann K, Trahair T, Liu T, Haber M, Norris MD, Woo AJ, Hogg P, Wang J and Wang JY. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia. 2019. 33:1400-1410. (IF 12.8)

• Gonzales-Aloy E, Connerty P,Salik B, Liu B, Woo AJ, Haber M,Norris MD, WangJ and Wang JY. miR-101 suppresses the development of MLL-rearranged acute myeloid leukemia. Haematologica. 2019. 104:296-299. (IF 11.04)

• Wong M, Sun Y, Xi Z, Milazzo G, Poulos RC, Bartenhagen C, Bell JL, Mayoh C, Ho N, Tee AE, Chen X, Li Y, Ciaccio R, Liu PY, Jiang CC, Lan Q, Jayatilleke N, Cheung BB, Haber M, Norris MD, Zhang XD, Marshall GM, Wang JY, Hüttelmaier S, Fischer M, Wong JWH, Xu H, Giovanni Perini, Qihan Dong, George RE, Liu T. JMJD6is a tumorigenic factor and therapeutic target in neuroblastoma. Nature Communications. 2019. 10:3319. (IF 14.7)

• Liu P, Tee A, Milazzo G, Hannan K, Maag J, Mondal S, Atmadibrata B, Bartonicek N, Peng H, Ho N, Mayoh CM, Ciaccio R, Sun Y, Henderson M, Gao J, Everaert C, Hulme A, Cheung B, Shi L, Wang JY, Simon T, Fischer M, Zhang XD, Marshall G, Norris M, Haber M, Vandesompele J, Li J, Mestdagh P, Hannan R, Dinger M, Perini G, and LiuT. The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35. Nature Communications. 2019. 10:5026. (IF 14.7)

• Woo AJ, Patry C, Ghamari A, Pregernig G, Zheng K, Piers T, Hibbs M, Li JK, Fidalgo M, Wang JY, Lee J, Leedman PJ, Wang J, Fraenkel E, and Cantor AB. Zfp281 (ZBP-99) plays a functionally redundant role with Zfp148 (ZBP-89) during erythroid development. Blood Advances. 2019. 3:2499-2511. (IF 7.4)

2017

• Wong MK,Tee AE,Milazzo G,Bell JL,Poulos RC, Atmadibrata B, Sun Y, Jing D, Ho N, Ling D, Liu PY, Zhang XD,Hüttelmaier S,Wong JW, Wang JY,Polly P,Perini G,Scarlett CJ, Liu T. The histone methyltransferase DOT1L promotes neuroblastoma by regulating gene transcription.Cancer Research. 2017.77:2522-2533. (IF 12.5)

• Sun Y, Atmadibrata B, Yu D, Wong MKK, Liu B, Ho N, LingD, TeeAE, WangJY, Mungrue IN, Liu PY, Liu T. Up-regulation of LYAR induces neuroblastoma cell proliferation and survival. Cell Death & Differentiation. 2017. 24:1645-1654. (IF 13.7)

2016

• Lynch JR, Yi H, Casolari DA, Voli F, Gonzales-Aloy E, Fung TK, Liu B, Brown A, Liu T, Haber M, Norris MD, Lewis ID, So CWE, D’Andrea RJ, Wang JY. Gaq signaling is required for the maintenance of MLL-AF9 induced acute myeloid leukemia. Leukemia. 2016. 30:1745-1748. (IF 12.8)

• Lynch JR, Wang JY. G protein-coupled receptor signaling in stem cells and cancer. Int J Mol Sci. 2016. 17:707. (IF 5.6)

2014

• Dietrich PA, Yang C, Leung HH, Lynch JR, Gonzales E, Liu B, Haber M, Norris MD, Wang J, Wang JY. GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood. 2014. 124:3284-3294. (IF 21)

2006-2011

• Lane SW*, Wang JY*, Lo Celso C*, Ragu C, Bullinger L, Sykes SM, Ferraro F, Shterental S, Lin CP, Gilliland DG, Scadden DT, Armstrong SA, Williams DA. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011. 118:2849-2856.*Equal contribution (IF 21)
• Wang JY, Krivtsov AV, Sinha AU, North TE, Feng Z, Zon LI, Armstrong SA. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010. 327:1650-1653. (IF 44.7)
• Krivtsov AV, Wang JY, Feng Z, Armstrong SA. Gene expression profiling of leukemia stem cells. Methods Mol Biol. 2009. 538:231-246.
• Krivtsov AV, Wang JY, Feng Z, and Armstrong SA (2009) Gene expression profiling of leukemia stem cells. In: Leukemia Methods and Protocols. So C.W.E (Editor). Springer Publishing. (ISBN: 978-1-59745-418-6).
• Wang JY, Armstrong SA. Cancer: inappropriate expression of stem cell programs. Cell Stem Cell. 2008. 2: 297-299. (IF 19.8)
• Wang JY, Armstrong SA. Genome-wide SNP analysis in cancer: leukemia shows the way. Cancer Cell. 2007. 11:308-309. (IF 48.8)
• Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang JY, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006. 442:818–822. (IF50.5)

Book Chapter

Yang J, Hassan N, Chen SXF, Datuin J, Wang JY. Self-renewal pathways in acute myeloid leukemia stem cells. In Pier Paolo Piccaluga (Eds.), Acute Leukemias.Rijeka, Croatia: InTech Publishers. Book Chapter. 2020. doi:10.5772/intechopen.94379.