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 (Lu X et al., Virology 2000; Lu X et al., Journal of Virology 2001).  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. I was fascinated by the complex function and regulation of the p53 tumor suppressor. My initial work contributed to an important Nature research article concerning the role of p53 on organismal aging (Tyner S et al., Nature 2001), which was reported by a number of mainstream media such as BBC, Washington Post, and New York Times. Since then, I have been looking into molecular mechanisms for the induction and hemostatic regulation of p53.  My early work 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).  In the past decade, my research has been 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, profiled by Nature Rev Cancer, Nature Rev Clin Oncol, and Cancer Discov). 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.

Noncoding RNAs and DNA damage response - I have also been very interested in the roles of non-coding RNAs in the DNA damage response and human tumorigenesis. I was the first to identify a RNA-binding protein (RBP), KSRP, as a key player that translates DNA damage signaling to microRNA biogenesis (Zhang X, et al, Mol Cell 2011; Wan G et al., Trends Biochem Sci, Wan G et al, Cell Reports 2013). Given a higher level of complexity on the sequences and structures of pri-miRNAs, the processing specificity of miRNAs is primarily attributed to the Drosha complex in miRNA maturation. Regulatory RBPs in the Drosha complex are the key factors that determine the expression of specific miRNAs. In my laboratory, we have identified several important RBPs that recruit specific pri-miRNA for processing. For example, DDX1 promotes the expression of a subset of miRNAs that are associated with ovarian cancer progression and metastasis (Han C et al., Cell Reports 2014). We have also investigated a number of novel noncoding RNAs in the epigenetic regulation of gene expression (Wan G, et al., EMBO J, 2013).

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).

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.      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, Epub ahead of print.

2.      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.

3.      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.

4.      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.

5.      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.

6.      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.

7.      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).

8.      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.

9.      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.

10.  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.

11.  Wan G, Mathur R, Hu X, Zhang X, Lu X (2011). microRNA response to DNA damage. Trends in Biochemical Sciences, 36(9):478-84.

12.  Zhang X, Berger FG, Yang J, Lu X (2011). USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO Journal, 30(11):2177-89.

13.  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).

14.  Zhang W, Gilstrap K, Wu L, K C RB, Moss M, Wang Q, Lu X, He X (2010).  Synthesis and characterization of thermally responsive Pluronic-chitosan nanocapsules for controlled release and intracellular delivery of small molecules. ACS Nano, 4(11):6747-59.

15.  Zhang X, Wan G, Mlotshwa S, Vance V, Berger F, Chen H, Lu X (2010). Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA Damage Signaling pathway. Cancer Research, 70(18):7176-86. 

16.  Zhang X, Lin L, Guo H, Jones SN, Jochemsen A, Lu X (2009). Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. Cancer Research, 69(20):7960-8.

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.  Lu X, Xiong Y, Silver J. (2002). Asymmetric requirement for cholesterol in receptor- bearing but not envelope-bearing membranes for fusion mediated by ecotropic murine leukemia virus. Journal of Virology, 76(13): 6701-9.

21.  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.

22.  Lu X and Silver J (2000). Ecotropic murine leukemia virus receptor is physically associated with caveolin and membrane rafts. Virology, 276(2): 251-8 (featured as cover story).

 

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