Xiongbin Lu

Xiongbin Lu, PhD

Vera Bradley Foundation Professor of Breast Cancer Innovation

Bio

I have been enjoying the dynamic and challenging nature of cancer research, which drives me to do something that is new and important at each stage of my academic career. I was trained as a virologist with emphasis on viral entry and infectivity.  After my first postdoctoral training at NIAID/NIH, I decided to take a challenge to study cancer biology in Dr. Donehower’s laboratory where the first p53 knockout mouse was generated. My initial work contributed to an important Nature research article concerning the role of p53 on organismal aging (Tyner S et al., Nature 2001). Soon after, I determined that Wip1 phosphatase is a master inhibitor in the ATM-p53 signaling pathway. It established a foundation to screen small chemical compounds for preclinical and clinical studies in cancer treatment (Lu X et al., Mol Cell 2004; Lu X et al., Genes & Dev 2005; Lu X et al., Cancer Cell 2007).  My current research is focused on the following fields:

Cancer Genomics and targeted therapy - Genomic instability is one of the most pervasive characteristics of cancer cells. In my laboratory, we have been studying DNA damage response and cancer genomic alterations (translocation, amplification, and deletion).  My recent work revealed that frequent hemizygous deletion of the p53 gene often encompasses a neighboring essential gene, POLR2A, rendering cancer cells vulnerable to further suppression of POLR2A (Liu Y et al., Nature 2015; Li Y et al., Nature Communications 2018). In collaboration with physician scientists and bioengineering scientists, we are now developing antibody-drug conjugates that specifically target human cancers with hemizygous loss of p53/POLR2A. Through bioinformatics analysis of human cancer genomes and experimental validation, we have also identified therapeutic vulnerabilities in many types of human cancer including prostate cancer, Ewing’s sarcoma, urinary bladder cancer, and breast cancer (Liu Y et al, JCI 2018; Liu Y et al, Nature Communications 2018).

Nanodrugs for cancer therapy - My laboratory has been collaborating with biomedical engineering scientists to develop nanoscale biomaterials to safely and effectively deliver one or more small and macromolecules including hydrophilic/hydrophobic anticancer drugs, proteins/peptides, and siRNAs/miRNAs. For example, we have synthesized dual (temperature and pH) responsive polymeric nanoparticles with a core-shell morphology to co-encapsulate both hydrophilic and hydrophilic drugs for targeting tumors and the drug resistance mechanisms of cancer (Zhang W et al., ACS Nano 2010; Rao W et al.,  ACS Nano 2015). Moreover, we have been working on combined cancer treatment of chemo, photodynamic, and photothermal therapies. We have developed a biomimetic hybrid nanoplatform with a eukaryotic cell-like configuration (Eukacell) and a NIR-laser activatable “nanobomb” for controlled release of small RNAs (Wang H et al., Nature Communications 2015; Wang H et al., Advanced Materials 2016; Agarwal P et al., ACS Nano 2017; Wang H et al., Nature Communications 2018).

Cancer omics and cancer immunology- We are interested to identify cancer gene signatures and tumor microenvironment that impact the infiltration of tumor-associated lymphocytes. Somatic mutations can give rise to neoantigens that are capable of eliciting potent T cell responses driven by current immunotherapies. However, mutations or aberrant gene expression in tumors can also induce resistance to immunotherapies. Clinical databases including cancer genomics, RNA-seq, proteomics, and tumor imaging are now analyzed to identify potential cancer gene signatures that are responsible for tumor-infiltration of cytotoxic lymphocyte. In vitro cytotoxicity assays, tumor organoid models, and in vivo tumor models (syngeneic tumor models and humanized mouse models) will be applied to determine the essential genes for tumor-associated lymphocyte penetration.

My laboratory will continue these efforts in understanding cancer biology, identifying novel drug targets and therapies, and developing new cancer drugs using innovative nanoscale biomaterials.

 

Key Publications

1. Liu Y, Xu J, Choi HH, Han C, Fang Y, Li Y, Van der Jeught K, Xu H, Zhang L, Frieden M, Wang L, Eyvani H, Sun Y, Zhao G, Zhang Y, Liu S, Wan J, Huang C, Ji G, Lu X*, He X*, Zhang X* (2018). Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer. Nature Communications, 9(1): 4718 (*Co-corresponding authors).
2. Li Y, Liu Y, Xu H, Jiang G, Van der Jeught K, Fang Y, Zhou Z, Zhang L, Frieden M, Wang L, Luo Z, Radovich M, Schneider BP, Deng Y, Liu Y, Huang K, He B, Wang J, He X, Zhang X, Ji G, Lu X (2018). Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nature Communications, 9(1): 4394.
3. Liu Y, Xu H, Van der Jeught K, Li Y, Liu S, Zhang L, Fang Y, Zhang X, Radovich M, Schneider BP, He X, Huang C, Zhang C, Wan J, Ji G, Lu X (2018). Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in human cancer. Journal of Clinical Investigation, 128(7):2951-2965.
4. Agarwal P, Wang H, Sun M, Xu J, Zhao S, Liu Z, Gooch KJ, Zhao Y, Lu X, He X (2017). Microfluidics Enabled Bottom-Up Engineering of 3D Vascularized Tumor for Drug Discovery. ACS Nano, 11(7):6691-6702.
5. Yang L, Achreja A, Yeung T, Mangala LS, Jiang D, Han C, Baddour J, Marini J, Ni J, Nakahara R, Wahlig S, Chiba L, Kim SH, Morse J, Pradeep S, Nagaraja AS, Haemmerle M, Kyunghee N, Derichsweiler M, Plackemeier T, Mercado-Uribe I, Lopez-Berestein G, Moss T, Ram PT, Liu J, Lu X, Mok SC, Sood AK, Nagrath D (2016). Targeting Glutamine Synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metabolism, 24(5):685-700.
6. Han C, Yang L, Choi HH, Baddour J, Achreja A, Liu Y, Li Y, Li J, Wan G, Huang C, Zhang X, Nagrath D, Lu X (2016). Amplification of USP13 drives ovarian tumor metabolism. Nature Communications, 7:13525.
7. Wang H, Agarwal P, Zhao S, Yu J, Lu X, He X (2016). A near infrared laser-activatable "nanobomb" for breaking the barriers to microRNA delivery. Advanced Materials, 28(2):347-55.
8. Wang H, Agarwal P, Zhao S, Yu J, Lu X, He X (2015). A biomimetic hybrid nanoplatform for encapsulation and precisely controlled delivery of theranostic agents. Nature Communications, 6:10081.
9. Rao W, Wang H, Han J, Zhao S, Dumbleton J, Agarwal P, Zhang W, Zhao G, Yu J, Zynger DL, Lu X, He X (2015). Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells. ACS Nano, 9(6):5725-40.
10. Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, Maru DM, Pahl A, He X, Sood AK, Ellis LM, Anderl J, Lu X (2015). TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature, 520(7549):697-701 (highlighted in Nature Reviews Cancer, Nature Reviews Clinical Oncology and Cancer Discovery).
11. Han C, Liu Y, Wan G, Choi HJ, Zhao L, Ivan C, He X, Sood AK, Zhang X, Lu X (2014). The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Reports, 8(5):1447-60.
12. Wan G, Hu X, Liu Y, Han C, Sood AK, Calin GA, Zhang X, Lu X (2013). A novel non-coding RNA lncRNA-JADE connects DNA damage signalling to histone H4 acetylation. EMBO Journal, 32(21):2833-47.
13. Wan G, Zhang X, Langley RR, Liu Y, Hu X, Han C, Peng G, Ellis LM, Jones SN, Lu X (2013). DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Reports, 3(6):2100-12.
14. Wan G, Mathur R, Hu X, Zhang X, Lu X (2011). microRNA response to DNA damage. Trends in Biochemical Sciences, 36(9):478-84.
15. Zhang X, Berger FG, Yang J, Lu X (2011). USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO Journal, 30(11):2177-89.
16. Zhang X, Wan G, Berger FG, He X, Lu X (2011). The ATM kinase induces microRNA biogenesis in the DNA damage response. Molecular Cell, 41:371-83 (commentary in the same issue and recommended by Faculty of 1000).
17. Lu X*, Ma O, Nguyen T, Jones SN. Oren M, Donehower LA (2007). The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell, 12(4):342-54 (profiled in Nature Reviews Cancer, * corresponding author).
18. Lu X, Nannenga B., Donehower LA (2005). PPM1D dephosphorylates CHK1 and p53 and abrogates cell cycle checkpoints. Genes & Development, 19(10): 1162-74 (profiled in Nature Reviews Cancer and recommended by the Faculty of 1000).
19. Lu X, Bocangel D, Nannenga B, Yamaguchi H, Appella E, Donehower LA (2004). The p53-Induced Oncogenic Phosphatase PPM1D Interacts with Uracil DNA Glycosylase and Suppresses Base Excision Repair. Molecular Cell, 15(4): 621-34.
20. Tyner S, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Karsenty G, Bradley A, Donehower LA (2002), p53 mutant mice that display early ageing-associated phenotypes (reported by Washington Post, New York Times, and BBC News). Nature, 415(6867): 45-53.

Connect


xiolu@iu.edu 


(317) 274-4398 


Medical & Molecular Genetics
R3-C218D MMGE
Indianapolis, IN


  

Titles & Appointments

  • Professor of Medical & Molecular Genetics
  • Professor with Tenure
  • Vera Bradley Foundation Chair in Breast Cancer Innovation
  • Strategic Research Initiative Distinguished Investigator