Steven D Leach

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Are you Steven D Leach?

Claim your profile

Publications (151)1111.26 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Feeling a bit cagey: morpholino-based antisense reagents have been caged through oligonucleotide cyclization, enabling photocontrol of gene expression in zebrafish embryos and larvae. Using these reagents, the timing of exocrine cell fate commitment in the developing pancreas has been examined.
    Angewandte Chemie International Edition 07/2012; 51(28):6908-11. DOI:10.1002/anie.201201690 · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review summarizes our current understanding of exocrine pancreas development, including the formation of acinar, ductal and centroacinar cells. We discuss the transcription factors associated with various stages of exocrine differentiation, from multipotent progenitor cells to fully differentiated acinar and ductal cells. Within the branching epithelial tree of the embryonic pancreas, this involves the progressive restriction of multipotent pancreatic progenitor cells to either a central "trunk" domain giving rise to the islet and ductal lineages, or a peripheral "tip" domain giving rise to acinar cells. This review also discusses the soluble morphogens and other signaling pathways that influence these events. Finally, we examine centroacinar cells as an enigmatic pancreatic cell type whose lineage remains uncertain, and whose possible progenitor capacities continue to be explored.
    Seminars in Cell and Developmental Biology 06/2012; 23(6):711-9. DOI:10.1016/j.semcdb.2012.06.008 · 5.97 Impact Factor
  • Cancer Research 04/2012; 72(8 Supplement):2968-2968. DOI:10.1158/1538-7445.AM2012-2968 · 9.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dicer is a ribonuclease whose major role is to generate mature microRNAs, although additional functions have been proposed. Deletion of Dicer leads to embryonic lethality in mice. To study the role of Dicer in adults, we generated mice in which administration of tamoxifen induces deletion of Dicer. Surprisingly, disruption of Dicer in adult mice induced lipid accumulation in the small intestine. To dissect the underlying mechanisms, we carried out miRNA, mRNA, and proteomic profiling of the small intestine. The proteomic analysis was done using mice metabolically labeled with heavy lysine (SILAC mice) for an in vivo readout. We identified 646 proteins, of which 80 were up-regulated >2-fold and 75 were down-regulated. Consistent with the accumulation of lipids, Dicer disruption caused a marked decrease of microsomal triglyceride transfer protein, long-chain fatty acyl-CoA ligase 5, fatty acid binding protein, and very-long-chain fatty acyl-CoA dehydrogenase, among others. We validated these results using multiple reaction monitoring (MRM) experiments by targeting proteotypic peptides. Our data reveal a previously unappreciated role of Dicer in lipid metabolism. These studies demonstrate that a systems biology approach by integrating mouse models, metabolic labeling, gene expression profiling, and quantitative proteomics can be a powerful tool for understanding complex biological systems.
    Journal of Proteome Research 02/2012; 11(4):2193-205. DOI:10.1021/pr2009884 · 5.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
    Cell 01/2012; 148(1-2):349-61. DOI:10.1016/j.cell.2011.11.025 · 33.12 Impact Factor
  • Jennifer M. Bailey, Steven D. Leach
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is an extremely aggressive disease characterized by a complex stromal or desmoplastic response. This dense desmoplastic response is in part the result of pancreatic stellate cell activation in response to paracrine signals from pre- neoplastic and neoplastic pancreatic epithelium. Activated stellate cells secrete a large array of soluble factors that directly influence malignant epithelial, vascular and inflammatory cells, and also alter the composition of the extracellular matrix. Thus, the signaling interactions between tumor and stellate cells represent a large, diverse spectrum of bidirectional and reciprocal influences necessary for the initiation and promotion of pancreatic cancer. A number of pathways including Hedgehog, Notch and Transforming growth factor-beta are involved in mediating cross-talk between the malignant pancreatic epithelium and its associated stroma, making them unique pathways to target for the treatment of pancreatic cancer.
    Pancreatic Cancer and Tumor Microenvironment, Edited by Paul J. Grippo, Hidayatullah G. Munshi, 01/2012: chapter Chapter 7; Transworld Research Network., ISBN: 9788178955483
  • Developmental Biology 08/2011; 356(1):224-224. DOI:10.1016/j.ydbio.2011.05.368 · 3.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The intracellular protein p120ctn controls cell–cell adhesion by regulation of E-cadherin stability. p120ctn binds to the juxtamembrane region of E-cadherin and regulates its retention at the cell–cell surface. Mice null for p120ctn are not viable. Using Pdx1:Cre and a conditional allele of p120ctn, we deleted p120ctn in all epithelial lineages of the developing mouse pancreas: islet, acinar, and ductal. Loss of p120ctn in the developing pancreas results in expansion of ductal epithelia and loss of acinar cells. Defects in branching morphogenesis are evident at E12.5. During development the phenotype becomes more severe, ultimately resulting in a pancreas comprised primarily of abnormal ductal tissue. Pdx1:Cre; p120ctn fl/fl animals are born dead. Loss of p120ctn results in mislocalization of E-cadherin and loss of b-catenin. Additionally, at E17.5 we observed broad expression of Sox9 and Pdx in Pdx1:Cre; p120ctn fl/fl animals. This suggests inappropriate persistence of progenitor cells at late developmental timepoints. Taken together, our data demonstrates an essential role for p120ctn in pancreatic acinar cell development and differentiation.
    Developmental Biology - DEVELOP BIOL, Chicago, Illinois; 08/2011
  • Source
    Bidyut Ghosh, Steven D Leach
    [Show abstract] [Hide abstract]
    ABSTRACT: Comment on: Andreia V. Pinho, et al. Cell Cycle 2011; 10: In press.
    Cell cycle (Georgetown, Tex.) 06/2011; 10(11):1717. DOI:10.4161/cc.10.11.15686 · 5.01 Impact Factor
  • Cancer Research 04/2011; 71(8 Supplement):2449-2449. DOI:10.1158/1538-7445.AM2011-2449 · 9.28 Impact Factor
  • Shu Liu, Steven D Leach
    [Show abstract] [Hide abstract]
    ABSTRACT: First established as a valuable vertebrate model system for studying development, zebrafish have emerged as an attractive animal system for modeling human cancers. Major technical advances have been essential for the generation of zebrafish cancer models relevant to human diseases. These models develop tumors in various organ sites that bear striking resemblance to human malignances, both histologically and genetically. Thus, the focus of cancer research in zebrafish has transcended the need to validate zebrafish as a viable model organism to study cancer biology. With the significant advantages of in vivo imaging, the power of forward genetics, well-established high efficiency for transgenesis, and ease of transplantation, further exploration of the zebrafish cancer models not only will generate unique insights into underlying mechanisms of cancer but will also provide platforms useful for drug discovery.
    Annual Review of Pathology Mechanisms of Disease 02/2011; 6:71-93. DOI:10.1146/annurev-pathol-011110-130330 · 22.13 Impact Factor
  • Cancer Research 01/2011; 70(8 Supplement):4162-4162. DOI:10.1158/1538-7445.AM10-4162 · 9.28 Impact Factor
  • Shu Liu, Steven D Leach
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in a majority of tumors. KRAS mutations represent an early event during pancreatic tumorigenesis, crucial for cancer initiation and progression. Recent studies, including comprehensive sequencing of the pancreatic cancer exome, have implicated the involvement of a number of additional core signaling pathways during pancreatic tumorigenesis. Improving our understanding of genetic interactions between KRAS and these additional pathways represents a critical challenge, as these interactions may provide novel opportunities for diagnosis and treatment. However, studying these interactions requires the expression of multiple transgenes in relevant cell types, an effort that has proven very difficult to achieve using gene targeted mice and is also technically challenging in zebrafish. Based on the ability of the Gal4 transcriptional activator to drive the expression of multiple transgenes under regulation of UAS (upstream activator sequence) regulatory elements, the Gal4/UAS system represents an attractive strategy for the study of genetic interactions. In this chapter, we review our experience using the Gal4/UAS system to model KRAS-initiated pancreatic cancer in zebrafish, as well as our early efforts using this system to study the influence of other cooperating oncogenes. We also describe techniques used to identify and characterize pancreatic tumors in adult transgenic fish.
    Methods in cell biology 01/2011; 105:367-81. DOI:10.1016/B978-0-12-381320-6.00015-1 · 1.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.
    Genes & development 12/2010; 24(24):2754-9. DOI:10.1101/gad.1950610 · 12.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The strength of functional imaging lies in its ability to detect malignant disease irrespective of lesion morphology. In this setting, 18FDG-PET can complement management by providing a more accurate diagnosis. When combined as an adjunct to CT, 18FDG-PET can increase the sensitivity, specificity, and accuracy for detecting a pancreatic malignancy, especially in patients in whom CT alone fails to identify a discrete mass or in whom biopsy results are indeterminate. This capability is accentuated with small lesions of the pancreas. 18FDG-PET is significantly more sensitive in detecting metastatic disease than conventional CT imaging. Moreover, 18FDG-PET is able to differentiate tumor response to therapy in the postoperative setting, and could potentially serve to monitor recurrence patterns in the setting of neoadjuvant or adjuvant chemoradiotherapy. Finally, as 18FDG-PET/CT fusion modalities become more widespread and technical advances in image acquisition progress, 18FDG-PET will continue to have an increasing role in the diagnosis, staging, and surveillance of pancreatic cancer, integrating anatomic information with functional imaging.
    Advances in Surgery 09/2010; 44:313-25. DOI:10.1016/j.yasu.2010.05.007
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing "pancreatospheres" in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas.
    Proceedings of the National Academy of Sciences 12/2009; 107(1):75-80. DOI:10.1073/pnas.0912589107 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Embryonic development of the pancreas is marked by an early phase of dramatic morphogenesis, in which pluripotent progenitor cells of the developing pancreatic epithelium give rise to the full array of mature exocrine and endocrine cell types. The genetic determinants of acinar and islet cell lineages are somewhat well defined; however, the molecular mechanisms directing ductal formation and differentiation remain to be elucidated. The complex ductal architecture of the pancreas is established by a reiterative program of progenitor cell expansion and migration known as branching morphogenesis, or tubulogenesis, which proceeds in mouse development concomitantly with peak Pdx1 transcription factor expression. We therefore evaluated Pdx1 expression with respect to lineage-specific markers in embryonic sections of the pancreas spanning this critical period of duct formation and discovered an unexpected population of nonislet Pdx1-positive cells displaying physical traits of branching. We then established a 3D cell culture model of branching morphogenesis using primary pancreatic duct cells and identified a transient surge of Pdx1 expression exclusive to branching cells. From these observations we propose that Pdx1 might be involved temporally in a program of gene expression sufficient to facilitate the biochemical and morphological changes necessary for branching morphogenesis.
    Molecular biology of the cell 09/2009; 20(22):4838-44. DOI:10.1091/mbc.E09-03-0203 · 5.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Zebrafish provide a highly versatile model in which to study vertebrate development. Many recent studies have elucidated early events in the organogenesis of the zebrafish pancreas; however, several aspects of early endocrine pancreas formation in the zebrafish are not homologous to the mammalian system. To better identify mechanisms of islet formation in the zebrafish, with true homology to those observed in mammals, we have temporally and spatially characterized zebrafish secondary islet formation. As is the case in the mouse, we show that Notch inhibition leads to precocious differentiation of endocrine tissues. Furthermore, we have used transgenic fish expressing fluorescent markers under the control of a Notch-responsive element to observe the precursors of these induced endocrine cells. These pancreatic Notch-responsive cells represent a novel population of putative progenitors that are associated with larval pancreatic ductal epithelium, suggesting functional homology between secondary islet formation in zebrafish and the secondary transition in mammals. We also show that Notch-responsive cells persist in the adult pancreas and possess the classical characteristics of centroacinar cells, a cell type believed to be a multipotent progenitor cell in adult mammalian pancreas.
    Mechanisms of development 08/2009; 126(10):898-912. DOI:10.1016/j.mod.2009.07.002 · 2.24 Impact Factor
  • Mechanisms of Development 08/2009; 126. DOI:10.1016/j.mod.2009.06.358 · 2.24 Impact Factor
  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)60144-X · 13.93 Impact Factor

Publication Stats

8k Citations
1,111.26 Total Impact Points

Institutions

  • 2014–2015
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2001–2014
    • Johns Hopkins University
      • • Department of Surgery
      • • McKusick-Nathans Institute of Genetic Medicine
      • • Department of Cell Biology
      Baltimore, Maryland, United States
  • 2001–2013
    • Johns Hopkins Medicine
      • • McKusick-Nathans Institute of Genetic Medicine
      • • Department of Surgery
      • • Department of Cell Biology
      • • Department of Pathology
      Baltimore, MD, United States
  • 2009
    • University of Pennsylvania
      • Division of Gastroenterology
      Philadelphia, PA, United States
  • 2008
    • Philipps University of Marburg
      Marburg, Hesse, Germany
    • Bryn Mawr College
      • Department of Biology
      Bryn Mawr, Pennsylvania, United States
  • 1998–2005
    • Vanderbilt University
      • • Department of Surgery
      • • Department of Radiology and Radiological Sciences
      • • Division of Surgical Oncology
      Nashville, MI, United States
  • 2004
    • University Pompeu Fabra
      Barcino, Catalonia, Spain
  • 2003
    • Mayo Foundation for Medical Education and Research
      • Department of Pathology
      Scottsdale, AZ, United States
  • 1997–2001
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
  • 1995–1998
    • University of Texas MD Anderson Cancer Center
      • • Department of Surgery
      • • Department of Surgical Oncology
      Houston, TX, United States