Dr. Wa Xian, Ph.D.

Dr. Wa Xian, Ph.D.

Assistant Professor, Center for Stem Cell & Regenerative Medicine; CPRIT Scholar in Cancer Research

Email Address: Wa.Xian@uth.tmc.edu
Phone Number: 713-500-3116
Room Number: SRB 630B

Narrative

Dr. Xian is building a broad platform of tissue-specific, adult stem cells for modeling human disease, drug discovery, and regenerative medicine.  In particular, she has developed innovative technologies that capture, for the first time, the most immature or “ground state” stem cells of human columnar epithelia including the gastrointestinal tract, liver, pancreas, and kidney.  She has demonstrated that these cells have properties that provide fundamental advantages for regenerative medicine in general and for patient-specific models of chronic and proliferative diseases in particular.  For regenerative medicine, she has shown that ground state, “adult” stem cells are readily clonogenic and that single clones or “pedigrees” have unlimited replicative potential, are genomically stable, and retain an exquisitely precise commitment to the multiple epithelial cell types found in the particular organ from which were derived.  In addition to these features, ground state stem cells have the remarkable property of recapitulating, in the absence of stromal cells, complex 3-D assemblies akin to that seen in the organ in vivo.  Based on this unique combination of properties, she anticipates that ground state epithelial stem cells will ultimately dominate efforts towards autologous transplantation therapies.  Dr. Xian is also working with clinical specialists and molecular geneticists in chronic inflammatory diseases of the airways and gastrointestinal tract to develop patient-specific disease models of these diseases which are already yielding profound insights into the roles of epithelia in the etiology and/or chronic features of these diseases.  They anticipate that the enhanced resolution of aberrant signaling pathways and epigenetic analyses afforded by these cloned, patient-specific stem cell models will provide new approaches to treatment of these chronic conditions.  Finally, Dr. Xian’s ground state stem cell technology is proving its value in capturing the minute “cancer stem cell” clones from the plurality of tumor cells from aggressive epithelial cancers of the ovary, pancreas, stomach, and lung to name several.  “Libraries” of such cancer stem cells from each patient are already providing insights into both the existence of sub-populations with intrinsic resistance to standard of care chemotherapy as well as rapid screens for alternative, effective treatments with the goal of suppressing or preventing recurrent disease.

Dr. Wa Xian received her Bachelor’s degree in Biochemistry from Nankai University in China and Ph.D. degree in Molecular Genetics at the University of Texas Graduate School of Biomedical Sciences in Houston, focusing on master regulator genes of cell proliferation and lineage specification during early neural development.  The support of a DOD breast cancer fellowship enabled Dr. Xian’s postdoctoral studies with Prof. Jeffrey Rosen at the Baylor College of Medicine.  There she used a combination of ligand-induced dimerization strategies and a mammary epithelial 3D culture system to address the role of fibroblast receptor tyrosine kinase signaling in the evolution of breast cancer. In 2008, Dr. Xian moved to Harvard Medical School under the direction of Prof. Christopher Crum, Director of Women’s and Perinatal Pathology at the Brigham and Women’s Hospital to study the origin and evolution of ovarian cancer.  Dr. Xian continues to work very closely with Prof. Crum on the origins and chemotherapy resistance problem in high-grade ovarian cancer.  In 2009, Dr. Xian was appointed Principal Investigator at the Institute of Medical Biology of the Agency for Science, Technology, and Research in Singapore, where she jointly oversaw a highly interactive group of postdoctoral fellows, graduate students, and research assistants with Prof Frank McKeon of the Genome Institute of Singapore devoted to the cloning of stem cells of regenerative tissues and using advanced technologies to understand the genetics of their self-renewal, commitment, and differentiation.  In 2013, Dr. Xian returned to the US and initiated multiple projects related to inflammatory diseases and cancer with colleagues at the University of Connecticut Health Center.  In  2015, Dr. Xian received the Rising Stars Award from the Cancer Prevention & Research Institute of Texas (CPRIT) and was recruited to the Institute of Molecular Medicine at the University of Texas Health Science Center in Houston.

Ongoing Research:

Stem Cell Mediated Lung Regeneration

Dr. Xian’s laboratory was instrumental in demonstrating the robust capacity of the lung to regenerate following massive acute injury due to H1N1 influenza virus infection (Kumar et al., Cell, 2011).  This result was unexpected due to the unremitting decline of patients with COPD and pulmonary fibrosis, but consistent with the dramatic recovery of many patients with acute lung damage from ARDS or necrotizing pneumonia.  Accompanying this regenerative process is a massive expansion of rare Krt5/p63 cells that migrate specifically to sites of infection and differentiate to form new alveoli.  These same cells can be cloned, expanded in vitro, and reintroduced to post-infection animals by intratracheal delivery, upon which the transplanted cells home to damaged regions to form new alveoli (Zuo et al., Nature, 2015).  These studies represent a first step towards an ultimate goal of regenerative medicine for acute and chronic lung diseases.

Patient-Specific Models of Inflammatory Diseases

Dr. Xian’s laboratory has recently devised transformative methods for cloning stem cells from the gastrointestinal tract (Wang et al., Nature, 2015).  In one revealing example of the utility of this model, she showed that colonic epithelium derived from a single colon stem cell pedigree could be converted by exposure to recombinant C. difficile toxins A or B to a pseudomembranous colitis, one of the pathognomonic features of C. difficile infections.  Her laboratory is now focused on cloning stem cells from patients with inflammatory bowel diseases for resolving the role of the epithelia in the initiation and maintenance of these conditions and the potential of regenerative medicine solutions to them.

Evolution and Resistance of Lethal Epithelial Cancers

Dr. Xian is also applying her stem cell cloning technology to understand the progression of epithelial cancers from non-cancerous precursors such as the Barrett’s esophagus that precedes, by several decades, the onset of esophageal adenocarcinoma (Wang et al., Cell, 2011).  These studies are designed to identify preemptive therapies directed at such lesions.   In addition, her laboratory is using stem cell technologies for generating libraries of cancer stem cells from patients with ovarian, pancreatic, gastric, and lung cancer.  These libraries are revealing markers and pathways operating in the cancer stem cell that are amenable to interdiction as well as subpopulations that have resistance to chemotherapy they have never been exposed to.  These studies could provide new approaches to cancers that have poor response to present therapies.      

Wang X, Yamamoto Y, Wilson LH, Zhang T, Howitt B, Farrow MA, Kern F, Ning G, Yue Hong, Khor CC, Chevalier B, Bertrand D, Niranjan N, Sylvester FA, Hyams JS, Devers T, Bronson R, Lacy DB, Ho KY, Crum CP, *McKeon F and *Xian W. (2015). Cloning and variation of ground state intestinal stem cells.  Nature. 522, 173-178 . (*communicating author)

Yamamoto Y, Ning G, Howitt BE, Mehra K, Wu L, Wang X, Hong Y, Kern F, Wei TS, Zhang T, Nagarajan N, Basuli D, Torti S, Brewer M, Choolani M, McKeon F, Crum CP, Xian W. (2015) In Vitro and In Vivo Correlates of Physiologic and Neoplastic Human Fallopian Tube Stem Cells. J Pathol. 2015 Sep 28

Zuo W, Wu DZ, Zhang T, Guan SP, Liew AA, Yamamoto Y, Lessard M, Crum CP, *Xian W, and *McKeon F. p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration. Nature. 2014  Nov 12. (*communicating author)

Ning G, Bijron J, Herfs M, Yamamoto Y, Howitt B, Yang E, Hanamornroongruang S, McKeon F, Crum CP, Xian W.  The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium. J Pathol. 2014 Dec;234(4):478-87.

Xian W, McKeon FD, Ho KY. 2013. Biomarkers and molecular imaging in gastrointestinal cancers. Clinical Gastroenterology and Hepatology. Clin Gastroenterol Hepatol.2013 Aug 23.  Invited Review.

Crum CP, Herfs M, Gang N, Bijron JG, Howitt B, Gasper C, Hanamornroongruang S, McKeon FD, Xian W. 2013. Through the glass darkly: intraepithelial neoplasia, top down differentiation, and the road to ovarian cancer. J Pathol. 2013 Sep 13. Invited Review.

Herfs M, Yamamoto Y, Laury A, Wang X, Nucci MR, McLaughlin-Drubin ME, Münger K, Feldman S, McKeon FD, *Xian W, *Crum CP.  2012.  A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci U S A. 109:10516-10521. (*communicating author). Faculty 1000 Biology: 6.5 (recommended).

Xian W, Ho YK, Crum CP, McKeon F.  2012.  Cellular origin of Barrett’s esophagus: Controversy and therapeutic implications. Gastroenterol. 142:1424-1430. Invited Review.

Crum CP, McKeon F, Xian W.  2012.  The oviduct and ovarian cancer: causality, clinical implications, and targeted prevention. Clin Ob Gyn 55: 24-35. PMCID: PMC3319355. Invited Review.

Xian W, McKeon F.  2012.  Adult stem cells underlying lung regeneration. Cell Cycle. 11(5):887-894. PMCID: PMC3323764. Invited Review.

Kumar PA, Hu Y, Yamamoto Y, Neo BN, Wei TS, Mu D, Sun Y, Lim SJ, Dagher R, Zielonka EM, Wang DY, Lim B, Chow VT, Crum CP, *Xian W, *McKeon F.  2011.  Distal airway stem cells render alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147:525-538. (*communicating author). Highlighted in Science (Editor’s Choice) and Nature.

Wang X, Ouyang H, Yamamoto Y, Kumar PA, Tay SW, Dagher R, Vincent M, Lu X, Ho YK, Crum CP, *Xian W, *McKeon F.  2011.  Residual embryonic cells as precursors of a Barrett’s-like metaplasia. Cell 145:1023-1035PMCID: PMC3125107. (*communicating author). Featured Article in Cell. Highlighted in Nature Reviews Cancer. Faculty 1000 Biology: 10 (Exceptional).

Xian W, Miron A, Roh M, Semmel DR, Yassin Y, Garber J, Oliva E, Goodman A, Mehra K, Berkowitz RS, Crum CP, Quade BJ.  2010.  The Li Fraumeni Syndrome (LFS): A model for the initiation of p53 signatures in the distal fallopian tube. J Pathol. 220:17-23; Cover story and editorial.

Xian W, Pappas L, Pandya D, Selfors L, Derksen PW, de Bruin M, Gray NS, Jonkers J, Rosen, JM, Brugge JS.  2009.  FGFR1-transformed mammary epithelial cells are dependent on RSK activity for growth and survival. Cancer Res. 69:2244-51.

Xian W, Schwertfeger KL, Rosen JM.  2007.  Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition. Mol Endocrinol. 21:987-1000; Cover story and editorial.

Xian W, Schwertfeger KL, Vargo-Gogola TC, Rosen JM.  2005.  Pleiotropic effects of FGFR1 on cell proliferation, survival and migration in a 3D mammary epithelial cells model. J Cell Biol. 171:663-673.