Xuanmao_Jiao.png

Xuanmao Jiao, Ph.D

Status

Dr. Xuanmao Jiao is currently the an Associate Professor in the Pennsylvania Cancer and Regenerative Medicine Research Center, a part of the Baruch S. Blumberg Institute in Doylestown, Pennsylvania.  He previously held the position of Instructor, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA

 

background

I have been involved with the first studies of DACH1 showing functional interaction with p53 and the role of Dach1 in stem cell function. I am an author on the issued patent on Dach1 in cancer. I have contributed directly to several publications relevant to this proposed grant.  Since joining the current lab, I have been working on the role of stem cell regulatory factors in cancer, primarily breast cancer including c-Jun and its related signal pathways including CCL5/CCR5, cyclin D1 and Dach1. I have examined these genetic factors in tumor metastasis, tumorigenesis and cancer stem cell self-renewal/expansion and have 31 original research papers published in peer-reviewed journal s. Before this, I worked on chemotaxis, vaccine development, liposome technology, membrane fusion and mitochondria functions. I have extensive expertise and thoroughly understanding on tumor metastasis, tumorigenesis, cancer stem cell, chemotaxis, vaccinology and liposome technology. My specific interest is using both living cell imaging and traditional immune-fluorescent staining technique to visualize biological process in single cell level which are well suited to the studies outlined in Aim 1 analyzing aged mitochondria dependent cell symmetry and Aim 2 assessing autophagy-dependent effects on BTIC . 

 

Contributions to Science

Prostate cancer: As prostate cancer onset and progression involves the mune system we developed a metastatic murine model that recapitulates human prostate cancer, both geneticaly and epigenetically, and metastasizes to bones and brain in the muse.. We demonstrated that in human prostate cancer cells the abundance of cyclin D1 is induced by growth factors and siRNA to cyclin D1 reduced ErbB2-mediated DNA synthesis in LNCaP cells (Cancer Research, 2007; 67(9):4364-4372)., that cyclin D1 restrains EMT and promotes stem cell expanding gene expression in the prostate. This may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer (Cancer Research, 2014; Jan 15; 74(2):508-19).

Dach1 and Cancer. Dach1 was initially cloned as a gene governing eye development. Dr. Pestell has led in the field of Dach1 in tumorigenesis. Pestell was the first to show that Dach1 restrains tumor growth, that the abundance of Dach1 is reduced in human cancers and that Dach1 restrains stem cells through reprogramming an Oct/Nanog/EKLF pathway. He was the first to show Dach1 binds to non-canonical TF binding sites (c-Jun, Smad) and bind DNA directly to promote gene expression modules. He showed Dach1 is phosphorylated and acetylated and controls breast cancer epithelial cell growth and migration in vitro and in vivo.

Androgen and Nuclear receptor acetylation. Dr. Pestell was the first to show nuclear receptors including the androgen receptor, are acetylated, that acetylation regulates contact-independent growth, and that this event is rate-limiting in hormone signaling and that acetylation is a general mechanism conserved among diverse nuclear receptors regulating diverse biological processes. Dr. Pestell proved that a single residue acetylated in the nuclear receptor, converted a growth suppressor into a growth activator. There have been >19,300 publications on nuclear receptor acetylation since our original discovery.

Cancer Stem cells. The Pestell lab has defined the requirement for specific target genes in the formation of breast and prostate epithelial cancer stems cells using transgenic or inducible knockout mice (NFκB, p21CIP1, c-jun) and have defined distinct roles for cyclin D1 in polarity vs stem cell function. These transgenic animals have been shared widely with the research community.

Cyclin D1 non canonical functions governing gene expression. Dr. Pestell has been a pioneer in the understanding of cell-cycle control in cancer. He was the first to show that: 1) cyclins are direct transcriptional targets of oncogenic and tumor suppressor signals; 2) cyclin D1 expression is rate-limiting for oncogeneinduced breast tumor and colon growth in vivo; 3) cyclin D1 binds DNA to regulate gene expression and chromosomal instability; 4) cyclins interact with nuclear receptors and tumor suppressors; 5) cyclins regulate mitochondrial metabolism, cellular migration, the non-coding genome and its biogenesis;

 

contributions to science

The role of Dach1 in breast and prostate cancer tumorigenesis and metastasis.

1.  Wu K, Katiya S, Li A, Liu M, Ju X, Popov V, Jiao X, Lisanti MP, Antonella, C, Pestell RG, Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8.  Proc. Nat Acad.Sci.USA, 2008,  105(19):6924-9.  Epub 2008 May 8.PMCID: PMC2374551.

2.  Wu K, Jiao X, Li A, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer stem cell function.J Biol Chem. 2011, 286(3):2132-42. Epub 2010 Oct 11. PMCID: PMC3023510.

3.  Wu K, Chen K, Wang C, Jiao X, Wang L, Zhou J, Wang J, Li Z, Addya S, Sorensen PH, Lisanti MP, Quong A, Ertel A, Pestell RG. Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation. Cancer Res.2014, 74(3):829-39. Epub 2013 Dec 12. PMCID: PMC3933065.

4.  Chen K, Wu K, Jiao X, Wang L, Ju X, Wang M, Di Sante G, Xu S, Wang Q, Li K, Sun X, Xu C, Li Z, Casimiro MC, Ertel A, Addya S, Mccue PA, Lisanti MP, Wang C, Davis RJ, Marden G, Pestell RG. The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via  repression of cytokine secretion via a cxcl signaling module. Cancer Res. 2015, 75(10):1992-2004. Epub 2015 Mar 13. PMCID: PMC4433595.

The Role of chemokine and chemokine receptor in cell migration and tumor metastasis. CCR5 antagonists, originally developed as HIV entry inhibitors, were found reducing invasiveness and metastastic capability of breast and prostate cancer cells both in vitro and in vivo, with immediate clinical implications for evaluation as anti-metastatic drugs. Ligand (IL-8)-induced partitioning of human CXCR 1 chemokine receptors to lipid raft facilitates G-protein-dependent signaling. The role of Pl3 kinase in chemoattractant gradient sensing.

5.  Jiao X, Zhang N, Xu X, Oppenheim JJ, Jin T, Ligand-induced partitioning of human CXCR1 chemokine receptors with lipid raft microenvironments facilitates G-protein-dependent signaling. Mol.Cell.Biol.2005, 25(13):5752-62.PMCID: PMC1156970.

6.  Xu X, Meier-Schellersheim M, Jiao X, Nelson L, Jin T, Quantitative imaging of single live cells reveals spatiotemporal dynamics of multi-step signaling events of chemoattractant gradient sensing in Dictyostelium,  Mol.Biol.Cell, 2005,  16(2):676-688.  PMCID: PMC545903.

7.  Velasco-Velazquez  M, Jiao X,  De La Fuente M, Pestell TG, Ertel A,  Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012, 72(15):3839-50, Epub 2012 May 25. (equal first author) PMCID: Identifier absent.

8.  Sicoli D, Jiao X, Ju X, Velasco-Velazquez M, Ertel A, AddyaS, Li Z, Ando S, Fatatis A, Paudyal B, Cristofanilli M,. Thakur ML, Lisanti MP, Pestell RG. CCR5 receptor antagonists block metastasis to bone of v-Src-oncogene- transformed metastatic prostate cancer cell lines. Cancer Res. 2014, 74(23):7103-14 (equal  first author).PMCID: PMC4294544.

The Role of c-Jun,a proto-oncogene, in breast cancer metastasis and tumorigenesis. c-Jun was found to induce mammary tumor cellular invasion and breast cancer stem cell expansion.Disruption of c-Jun reduces cellular migration and invasion through inhibition of c-Src and hyperactivation of ROCK IIKinase. c-Jun is also required for TGF-J3-mediated cellular migration via nuclear Ca2+ signaling and play the role in alternative splicing.

9.  Jiao X, Katiyar S, Liu M, Mueller SC, Lisanti MP, Li A, Pestell TG, Wu K, Ju X, Li Z, Wagner EF, Takeya T, Wang C, Pestell RG, Disruption of c-Jun Reduces Cellular Migration and Invasion through Inhibition of c-Src  and  Hyperactivation  of  ROCK  II  Kinase,  Mol. Biol.  Cell, 2008,  19(4):1378-1390.  PMCID: MC2291431.

10.  Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG. C-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem. 2010, 285(11):8218-8226. Epub 2010 Jan 6. PMCID: PMC2832973.

11.  Janowski E, Jiao X, Katiyar S, Lisanti MP, Liu M, Pestell RG, Morad M. c-Jun is required for TGF-f3- mediated cellular migration via nuclear Ca2 signaling. Int J Biochem Cell Biol. 2011, 43(8): 1104-13. Epub 2011Apr 5 (equal first author). PMCID: Identifier absent.

12.  Katiyar S, Jiao X,Addya S, ErtelA, Rose V, Casimiro MC, Zhou J,Lisanti MP, Nasim T,Fortina P,Pestell RG. Mammary gland selective excision of c-jun identifies its role in mRNA splicing. Cancer Res. 2012, 72(4):1023-342011, Epub 2011 Dec 15 (equal first author). PMCID: PMC3288968.

The role of cyclin 01 in DNA damage/repair, cell migration,EMT and stem cell expansion.

13.  Fu M, Wang C, Rao M, Wu X, Bouras T, Zhang X, Li Z, Jiao X, Yang J, Li A, Perkins ND, Thimmapaya B, Kung AL,Munoz A, Giordano A, Lisanti MP, Pestell RG, Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism, J. Biol.Chem., 2005, 280(33): 29728-42. PMCID: Identifier absent.

14.  Lindsay J, Jiao X, Sakamaki T, Casimiro MC, Shirley LA, Tran TH, Ju X, Liu M, Li Z, Wang C, Katiya S, Rao M, Allen KG, Glazer RI, Ge C, Stanley P, Lisanti MP, Rui H, Richard RG, Erb82 induces Notch1 activity and function in breast cancer cells, Clinical and Translational Science, 2008, 1(2):107-115. PMCID: PMC3590841.

15.  Ju X, Casimiro MC, Gormley M, Meng H, Jiao X, Katiyar S, Crosariol M, Chen K, Wang M, Quong AA, Lisanti MP, Ertel A, Pestell RG. Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint. Cancer Res. 2014, 74(2):508-19. Epub 2013 Nov 26. PMCID: PMC3914674.

16.  Li Z, Chen K, Jiao X, Wang C, Willmarth NE, Casimiro MC, Li W, Ju X, Kim SH, Lisanti MP, Katzenellenbogen JA, Pestell RG.Cyclin D1 integrates estrogen-mediated DNA damage repair signaling. Cancer Res. 2014, 74(14):3959-70. Epub 2014 May 15. PMCID: PMC4102655.