Basement Membrane; Drosophila; Genetics; Metabolism; Neoplasm Metastasis; Genomics
Stem Cell Center, Yale: Stem Cell Genetics
The Xu lab is is interested in utilizing model organisms to understand cancer biology and developmental mechanisms. In particular, the lab is developing and using new genetic approaches to identify genes that are involved in tumor growth and metastasis, and are exploring the developmental and biochemical functions of these genes.
Specialized Terms: Genetic methodology; Cancer biology; Food and metabolism; Developmental mechanisms
Extensive Research Description
Metastasis is the major cause of mortality for cancer patients. Given that alterations causing metastasis are late events and that multiple genetic alterations occur in late stage cancers, traditional approaches have not been fruitful in identifying genes involved in metastasis. We have performed a genome-wide genetic screen for mutations promoting tumor progression and metastasis in Drosophila and have identified mutations in more than 50 genes. We have found that apicobasal polarity mutations in collaboration with oncogenic Ras mutation produce fly tumors with a full spectrum of metastatic phenotypes observed in human malignant cancers. Mutation of cell polarity genes activates JNK signaling and down-regulates the E-cadherin/b-catenin adhesion complex. Furthermore, JNK and Ras signaling cooperate in promoting tumor growth. The concept that tumor-initiating alterations contribute to the development of metastasis, provides an explanation why tumors of distinguish origins have vast different metastatic potential.
Our work has also revealed that tumor cells hijack normal invasive developmental process to achieve progression. Elements of the invasion machinery, including JNK-induced MMP expression, are shared by both developmental and tumor invasion processes. Preventing BM degradation completely blocks both tissue and tumor invasion, indicating that modulation of BM is essential for invasion. The pathways regulate invasion during development and tumor progression are excellent targets for cancer therapy. Our work on tumor growth have shown that tumor suppressors such as TSC, PTEN, and LATS regulate tissue and organism size during development and propose that deregulation of size-control mechanisms is essential for tumorigenesis. We have showed that TSC and PTEN genes function in the PI3K/Akt pathway and reduction of S6K activity levitates TSC defects. These findings have helped to define one of the major cancer pathways in humans and have lead to clinical trials for TSC and LAM diseases. One of our long term goal is to develop methodologies in mammals for interrogating the genome by forward genetics. We have successfully adapted the piggyBac transposon for transgenesis and insertional mutagenesis in mammals. This has led to the development of a highly efficient single transposon mutagenesis strategy and to the near-production of the first set of genome-wide insertional mutants in mice, which will provide an unprecedented opportunity for deciphering mammalian biology and disease.
Interaction between RasV12 and scribble clones induces tumor growth and invasion.
Wu M, Pastor-Pareja JC & Xu T. Interaction between RasV12 and scribble clones induces tumor growth and invasion. Nature, 2010, 403, 676–680.
Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila.
Igaki T., Pastor-Pareja, JC., , Aonuma, H., Miura M. and Xu T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell, 2009, 16:458-465.
Efficient Transposition of the piggyBac (PB) Transposon in Mammalian Cells and Mice.
Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T. (2005). Efficient Transposition of the piggyBac (PB) Transposon in Mammalian Cells and Mice. Cell 122(3):473-483.
A genetic screen in Drosophila for metastatic behavior.
Pagliarini, R.A. and Xu, T. (2003). A genetic screen in Drosophila for metastatic behavior. Science 14:1227-31.
Drosophila Atrophin homolog functions as a transcriptional co-repressor in multiple developmental processes.
Zhang S, Xu L, Lee J, Xu T. Drosophila Atrophin homolog functions as a transcriptional co-repressor in multiple developmental processes. Cell 2002, 108:45-56.
Akt regulates growth by directly phosphorylating Tsc2.
Potter CJ, Pedraza LG,Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol 2002,4:658-665.
- Potter C J, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001, 105:357-368.
Full List of PubMed Publications
- Jin Y, Chen Y, Zhao S, Guan KL, Zhuang Y, Zhou W, Wu X, Xu T: DNA-PK facilitates piggyBac transposition by promoting paired-end complex formation. Proc Natl Acad Sci U S A. 2017 Jun 23; 2017 Jun 23. PMID: 28645898
- Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Xu T, Rothberg J, Lichenstein H: B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition. Autophagy. 2017 Jun 3; 2017 Mar 28. PMID: 28350209
- Li G, Ye Z, Shi C, Sun L, Han M, Zhuang Y, Xu T, Zhao S, Wu X: The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice. Sci Rep. 2017 Apr 4; 2017 Apr 4. PMID: 28374742
- Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T, Rothberg J, Lichenstein H: Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30; 2017 Jan 19. PMID: 28104689
- Zhu X, Xie S, Xu T, Wu X, Han M: Rasal2 deficiency reduces adipogenesis and occurrence of obesity-related disorders. Mol Metab. 2017 Jun; 2017 Mar 18. PMID: 28580280
- Chabu C, Li DM, Xu T: EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth. Nat Commun. 2017 Mar 10; 2017 Mar 10. PMID: 28281543
- Yang D, Liao R, Zheng Y, Sun L, Xu T: Analysis of PBase Binding Profile Indicates an Insertion Target Selection Mechanism Dependent on TTAA, But Not Transcriptional Activity. Int J Biol Sci. 2016; 2016 Jul 18. PMID: 27570481
- Wang G, Li R, Yang Y, Cai L, Ding S, Xu T, Han M, Wu X: Disruption of the Golgi protein Otg1 gene causes defective hormone secretion and aberrant glucose homeostasis in mice. Cell Biosci. 2016; 2016 Jun 10. PMID: 27293546
- Ye Z, Sun L, Li R, Han M, Zhuang Y, Wu X, Xu T: Generation of a Mouse Full-length Balancer with Versatile Cassette-shuttling Selection Strategy. Int J Biol Sci. 2016; 2016 Jun 7. PMID: 27489495
- Li S, Mo K, Tian H, Chu C, Sun S, Tian L, Ding S, Li TR, Wu X, Liu F, Zhang Z, Xu T, Sun LV: Lmod2 piggyBac mutant mice exhibit dilated cardiomyopathy. Cell Biosci. 2016; 2016 Jun 4. PMID: 27274810
- Liu Y, Li TR, Xu C, Xu T: Ribose Accelerates Gut Motility and Suppresses Mouse Body Weight Gaining. Int J Biol Sci. 2016; 2016 Apr 28. PMID: 27194947
- Willsey HR, Zheng X, Carlos Pastor-Pareja J, Willsey AJ, Beachy PA, Xu T: Localized JNK signaling regulates organ size during development. Elife. 2016 Mar 14; 2016 Mar 14. PMID: 26974344
- Tian L, Ding S, You Y, Li TR, Liu Y, Wu X, Sun L, Xu T: Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy. Dis Model Mech. 2015 Jun; 2015 Apr 16. PMID: 26035871
- Gayle S, Pan Y, Landrette S, Xu T: piggyBac insertional mutagenesis screen identifies a role for nuclear RHOA in human ES cell differentiation. Stem Cell Reports. 2015 May 12; 2015 Apr 9. PMID: 25866159
- Ye J, Shi H, Shen Y, Peng C, Liu Y, Li C, Deng K, Geng J, Xu T, Zhuang Y, Zheng B, Tao W: PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling. J Immunol. 2015 Feb 15; 2015 Jan 21. PMID: 25609840
- Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, Chi NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, Günel M: Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. Neuron. 2014 Dec 17. PMID: 25521378
- Chabu C, Xu T: Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth. Development. 2014 Dec; 2014 Nov 19. PMID: 25411211
- Olds WH, Xu T: Regulation of food intake by mechanosensory ion channels in enteric neurons. Elife. 2014 Oct 6; 2014 Oct 6. PMID: 25285450
- Shi F, Ding S, Zhao S, Han M, Zhuang Y, Xu T, Wu X: A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice. Hum Mol Genet. 2014 Jul 15; 2014 Feb 23. PMID: 24565867
- Ren J, Zhu H, Chi C, Mehrmohamadi M, Deng K, Wu X, Xu T: Beadex affects gastric emptying in Drosophila. Cell Res. 2014 May; 2014 Feb 25. PMID: 24566770
- Du X, Dong Y, Shi H, Li J, Kong S, Shi D, Sun LV, Xu T, Deng K, Tao W: Mst1 and mst2 are essential regulators of trophoblast differentiation and placenta morphogenesis. PLoS One. 2014; 2014 Mar 4. PMID: 24595170
- Choi J, Landrette SF, Wang T, Evans P, Bacchiocchi A, Bjornson R, Cheng E, Stiegler AL, Gathiaka S, Acevedo O, Boggon TJ, Krauthammer M, Halaban R, Xu T: Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. Pigment Cell Melanoma Res. 2014 Mar; 2014 Jan 6. PMID: 24283590
- Ding S, Xu T, Wu X: Generation of genetically engineered mice by the piggyBac transposon system. Methods Mol Biol. 2014. PMID: 25064103
- Ni TK, Landrette SF, Bjornson RD, Bosenberg MW, Xu T: Low-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma. Proc Natl Acad Sci U S A. 2013 Sep 17; 2013 Sep 3. PMID: 24003131
- Li R, Zhuang Y, Han M, Xu T, Wu X: piggyBac as a high-capacity transgenesis and gene-therapy vector in human cells and mice. Dis Model Mech. 2013 May; 2013 Mar 8. PMID: 23519027
- Xu T, Rubin GM: The effort to make mosaic analysis a household tool. Development. 2012 Dec. PMID: 23172911
- Pastor-Pareja JC, Xu T: Shaping cells and organs in Drosophila by opposing roles of fat body-secreted Collagen IV and perlecan. Dev Cell. 2011 Aug 16. PMID: 21839919
- Landrette SF, Xu T: Somatic genetics empowers the mouse for modeling and interrogating developmental and disease processes. PLoS Genet. 2011 Jul; 2011 Jul 21. PMID: 21814514
- Cornett JC, Landrette SF, Xu T: Characterization of fluorescent eye markers for mammalian transgenic studies. PLoS One. 2011; 2011 Dec 28. PMID: 22216292
- Landrette SF, Cornett JC, Ni TK, Bosenberg MW, Xu T: piggyBac transposon somatic mutagenesis with an activated reporter and tracker (PB-SMART) for genetic screens in mice. PLoS One. 2011; 2011 Oct 21. PMID: 22039523
- Chi C, Zhu H, Han M, Zhuang Y, Wu X, Xu T: Disruption of lysosome function promotes tumor growth and metastasis in Drosophila. J Biol Chem. 2010 Jul 9; 2010 Apr 25. PMID: 20418542
- Wu M, Pastor-Pareja JC, Xu T: Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature. 2010 Jan 28; 2010 Jan 13. PMID: 20072127
- Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T: Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell. 2009 Mar. PMID: 19289090
- Pastor-Pareja JC, Wu M, Xu T: An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis Model Mech. 2008 Sep-Oct; 2008 Sep 18. PMID: 19048077
- Nguyen D, Xu T: The expanding role of mouse genetics for understanding human biology and disease. Dis Model Mech. 2008 Jul-Aug. PMID: 19048054
- Xue L, Igaki T, Kuranaga E, Kanda H, Miura M, Xu T: Tumor suppressor CYLD regulates JNK-induced cell death in Drosophila. Dev Cell. 2007 Sep. PMID: 17765686
- Srivastava A, Pastor-Pareja JC, Igaki T, Pagliarini R, Xu T: Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion. Proc Natl Acad Sci U S A. 2007 Feb 20; 2007 Feb 14. PMID: 17301221
- Li P, Zhang HZ, Huff S, Nimmakayalu M, Qumsiyeh M, Yu J, Szekely A, Xu T, Pober BR: Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement. Am J Med Genet A. 2006 Dec 15. PMID: 17103440
- Igaki T, Pagliarini RA, Xu T: Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol. 2006 Jun 6. PMID: 16753569
- Busygina V, Suphapeetiporn K, Marek LR, Stowers RS, Xu T, Bale AE: Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. Hum Mol Genet. 2004 Oct 15; 2004 Aug 27. PMID: 15333582
- Yang X, Yu K, Hao Y, Li DM, Stewart R, Insogna KL, Xu T: LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nat Cell Biol. 2004 Jul; 2004 Jun 27. PMID: 15220930
- Pedraza LG, Stewart RA, Li DM, Xu T: Drosophila Src-family kinases function with Csk to regulate cell proliferation and apoptosis. Oncogene. 2004 Jun 10. PMID: 15107833
- Pagliarini RA, Xu T: A genetic screen in Drosophila for metastatic behavior. Science. 2003 Nov 14; 2003 Oct 9. PMID: 14551319
- Stewart RA, Li DM, Huang H, Xu T: A genetic screen for modifiers of the lats tumor suppressor gene identifies C-terminal Src kinase as a regulator of cell proliferation in Drosophila. Oncogene. 2003 Sep 25. PMID: 14508523
- Pagliarini RA, Quiñones AT, Xu T: Analyzing the function of tumor suppressor genes using a Drosophila model. Methods Mol Biol. 2003. PMID: 12777740
- Potter CJ, Pedraza LG, Xu T: Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002 Sep. PMID: 12172554
- Chen Q, Ma E, Behar KL, Xu T, Haddad GG: Role of trehalose phosphate synthase in anoxia tolerance and development in Drosophila melanogaster. J Biol Chem. 2002 Feb 1; 2001 Nov 21. PMID: 11719513
- Zhang S, Xu L, Lee J, Xu T: Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell. 2002 Jan 11. PMID: 11792320