Bio

Academic Appointments


  • Instructor, Institute for Stem Cell Biology and Regenerative Medicine

Honors & Awards


  • Siebel Scholar, Thomas and Stacey Siebel Foundation (2015-2016)
  • Postdoctoral Scholar Award, California Institute of Regenerative Medicine (CIRM) (2014-2015)
  • Postdoctoral Scholar Award, Damon Runyon Cancer Research Foundation (2011-2014)

Professional Education


  • Ph.D., UT Southwestern, Genetics and Development (2010)
  • B.S., National Taiwan University, Zoology (2001)

Research & Scholarship

Current Research and Scholarly Interests


Signaling network in adult stem cell niches.

Publications

All Publications


  • Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. Science (New York, N.Y.) Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W. J., Clarke, M. F., Beachy, P. A. 2017

    Abstract

    The stem cell niche is a complex local signaling microenvironment that sustains stem cell activity in organ maintenance and regeneration. The mammary gland niche must support its associated stem cells while also responding to systemic hormonal regulation that triggers pubertal changes. We find that Gli2, the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone. Whereas prior studies implicate stem cell defects in human disease, this work shows that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency (CPHD).

    View details for DOI 10.1126/science.aal3485

    View details for PubMedID 28280246

  • Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Proceedings of the National Academy of Sciences of the United States of America Lee, J. J., Rothenberg, M. E., Seeley, E. S., Zimdahl, B., Kawano, S., Lu, W., Shin, K., Sakata-Kato, T., Chen, J. K., Diehn, M., Clarke, M. F., Beachy, P. A. 2016

    Abstract

    Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+)Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

    View details for PubMedID 27815529

  • p53 genes function to restrain mobile elements GENES & DEVELOPMENT Wylie, A., Jones, A. E., D'Brot, A., Lu, W., Kurtz, P., Moran, J. V., Rakheja, D., Chen, K. S., Hammer, R. E., Comerford, S. A., Amatruda, J. F., Abrams, J. M. 2016; 30 (1): 64-77
  • Identification and Specification of the Mouse Skeletal Stem Cell CELL Chan, C. K., Seo, E. Y., Chen, J. Y., Lo, D., McArdle, A., Sinha, R., Tevlin, R., Seita, J., Vincent-Tompkins, J., Wearda, T., Lu, W., Senarath-Yapa, K., Chung, M. T., Marecic, O., Tran, M., Yan, K. S., Upton, R., Walmsley, G. G., Lee, A. S., Sahoo, D., Kuo, C. J., Weissman, I. L., Longaker, M. T. 2015; 160 (1-2): 285-298

    Abstract

    How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.

    View details for DOI 10.1016/j.cell.2014.12.002

    View details for Web of Science ID 000347923200025

  • p53 activity is selectively licensed in the Drosophila stem cell compartment ELIFE Wylie, A., Lu, W., D'Brot, A., Buszczak, M., Abrams, J. M. 2014; 3

    Abstract

    Oncogenic stress provokes tumor suppression by p53 but the extent to which this regulatory axis is conserved remains unknown. Using a biosensor to visualize p53 action, we find that Drosophila p53 is selectively active in gonadal stem cells after exposure to stressors that destabilize the genome. Similar p53 activity occurred in hyperplastic growths that were triggered either by the Ras(V12) oncoprotein or by failed differentiation programs. In a model of transient sterility, p53 was required for the recovery of fertility after stress, and entry into the cell cycle was delayed in p53(-) stem cells. Together, these observations establish that the stem cell compartment of the Drosophila germline is selectively licensed for stress-induced activation of the p53 regulatory network. Furthermore, the findings uncover ancestral links between p53 and aberrant proliferation that are independent of DNA breaks and predate evolution of the ARF/Mdm2 axis. DOI: http://dx.doi.org/10.7554/eLife.01530.001.

    View details for DOI 10.7554/eLife.01530

    View details for Web of Science ID 000332627400002

    View details for PubMedID 24618896

  • Meiotic Recombination Provokes Functional Activation of the p53 Regulatory Network SCIENCE Lu, W., Chapo, J., Roig, I., Abrams, J. M. 2010; 328 (5983): 1278-1281

    Abstract

    The evolutionary appearance of p53 protein probably preceded its role in tumor suppression, suggesting that there may be unappreciated functions for this protein. Using genetic reporters as proxies to follow in vivo activation of the p53 network in Drosophila, we discovered that the process of meiotic recombination instigates programmed activation of p53 in the germ line. Specifically, double-stranded breaks in DNA generated by the topoisomerase Spo11 provoked functional p53 activity, which was prolonged in cells defective for meiotic DNA repair. This intrinsic stimulus for the p53 regulatory network is highly conserved because Spo11-dependent activation of p53 also occurs in mice. Our findings establish a physiological role for p53 in meiosis and suggest that tumor-suppressive functions may have been co-opted from primordial activities linked to recombination.

    View details for DOI 10.1126/science.1185640

    View details for Web of Science ID 000278318600035

    View details for PubMedID 20522776

  • OPINION p53 ancestry: gazing through an evolutionary lens NATURE REVIEWS CANCER Lu, W., Amatruda, J. F., Abrams, J. M. 2009; 9 (10): 758-762

    Abstract

    Evolutionary patterns indicate that primordial p53 genes predated the appearance of cancer. Therefore, wild-type tumour suppressive functions and mutant oncogenic functions that give celebrity status to this gene family were probably co-opted from unrelated primordial activities. Is it possible to deduce what these early functions might have been? And might this knowledge provide a platform for therapeutic opportunities?

    View details for DOI 10.1038/nrc2732

    View details for Web of Science ID 000270102800013

    View details for PubMedID 19776745

  • The Bax/Bak ortholog in Drosophila, Debcl, exerts limited control over programmed cell death DEVELOPMENT Galindo, K. A., Lu, W., Park, J. H., Abrams, J. M. 2009; 136 (2): 275-283

    Abstract

    Bcl-2 family members are pivotal regulators of programmed cell death (PCD). In mammals, pro-apoptotic Bcl-2 family members initiate early apoptotic signals by causing the release of cytochrome c from the mitochondria, a step necessary for the initiation of the caspase cascade. Worms and flies do not show a requirement for cytochrome c during apoptosis, but both model systems express pro- and anti-apoptotic Bcl-2 family members. Drosophila encodes two Bcl-2 family members, Debcl (pro-apoptotic) and Buffy (anti-apoptotic). To understand the role of Debcl in Drosophila apoptosis, we produced authentic null alleles at this locus. Although gross development and lifespans were unaffected, we found that Debcl was required for pruning cells in the developing central nervous system. debcl genetically interacted with the ced-4/Apaf1 counterpart dark, but was not required for killing by RHG (Reaper, Hid, Grim) proteins. We found that debcl(KO) mutants were unaffected for mitochondrial density or volume but, surprisingly, in a model of caspase-independent cell death, heterologous killing by murine Bax required debcl to exert its pro-apoptotic activity. Therefore, although debcl functions as a limited effector of PCD during normal Drosophila development, it can be effectively recruited for killing by mammalian members of the Bcl-2 gene family.

    View details for DOI 10.1242/dev.019042

    View details for Web of Science ID 000261927500011

    View details for PubMedID 19088092

  • A collective form of cell death requires homeodomain interacting protein kinase JOURNAL OF CELL BIOLOGY Link, N., Chen, P., Lu, W., Pogue, K., Chuong, A., Mata, M., Checketts, J., Abrams, J. M. 2007; 178 (4): 567-574

    Abstract

    We examined post-eclosion elimination of the Drosophila wing epithelium in vivo where collective "suicide waves" promote sudden, coordinated death of epithelial sheets without a final engulfment step. Like apoptosis in earlier developmental stages, this unique communal form of cell death is controlled through the apoptosome proteins, Dronc and Dark, together with the IAP antagonists, Reaper, Grim, and Hid. Genetic lesions in these pathways caused intervein epithelial cells to persist, prompting a characteristic late-onset blemishing phenotype throughout the wing blade. We leveraged this phenotype in mosaic animals to discover relevant genes and establish here that homeodomain interacting protein kinase (HIPK) is required for collective death of the wing epithelium. Extra cells also persisted in other tissues, establishing a more generalized requirement for HIPK in the regulation of cell death and cell numbers.

    View details for DOI 10.1083/jcb.200702125

    View details for Web of Science ID 000248803600004

    View details for PubMedID 17682052

  • Lessons from p53 in non-mammalian models CELL DEATH AND DIFFERENTIATION Lu, W., Abrams, J. M. 2006; 13 (6): 909-912

    View details for DOI 10.1038/sj.cdd.4401922

    View details for Web of Science ID 000237703600007

    View details for PubMedID 16557266

  • The apical caspase dronc governs programmed and unprogrammed cell death in Drosophila DEVELOPMENTAL CELL Chew, S. K., Akdemir, F., Chen, P., Lu, W. J., Mills, K., Daish, T., Kumar, S., Rodriguez, A., Abrams, J. M. 2004; 7 (6): 897-907

    Abstract

    Among the seven caspases encoded in the fly genome, only dronc contains a caspase recruitment domain. To assess the function of this gene in development, we produced a null mutation in dronc. Animals lacking zygotic dronc are defective for programmed cell death (PCD) and arrest as early pupae. These mutants present a range of defects, including extensive hyperplasia of hematopoietic tissues, supernumerary neuronal cells, and head involution failure. dronc genetically interacts with the Ced4/Apaf1 counterpart, Dark, and adult structures lacking dronc are disrupted for fine patterning. Furthermore, in diverse models of metabolic injury, dronc- cells are completely insensitive to induction of cell killing. These findings establish dronc as an essential regulator of cell number in development and illustrate broad requirements for this apical caspase in adaptive responses during stress-induced apoptosis.

    View details for Web of Science ID 000225650700013

    View details for PubMedID 15572131