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Montagna Symposium 2011: 60th Anniversary—Advances in Science and Medicine Catalyzed by Pioneering Skin Research

      The 2011 Montagna Symposium, “Advances in Science and Medicine Catalyzed by Pioneering Skin Research,“ was the 60th Anniversary Meeting.
      The 2011 Montagna Symposium, “Advances in Science and Medicine Catalyzed by Pioneering Skin Research,” was held in Stevenson, Washington, USA, 13–17 October 2011. Information about content and support of past symposia and the next Montagna Symposium on the Biology of Skin can be found athttp://www.montagnasymposium.org.
      *The 2011 Montagna Symposium, “Advances in Science and Medicine Catalyzed by Pioneering Skin Research,” was held in Stevenson, Washington, USA, 13–17 October 2011. Information about content and support of past symposia and the next Montagna Symposium on the Biology of Skin can be found athttp://www.montagnasymposium.org.
      More than 120 scientists, clinicians, residents, students, and representatives from industry and the National Institutes of Health (NIH) attended. The three-day program included six sessions: (1) “Seminal Discoveries in Cancer Biology: DNA Repair,” (2) “Seminal Discoveries in Cancer Biology: Hedgehog Signaling,” (3) “Seminal Discoveries in Cancer Biology: Signal Transduction and Cancer Pathogenesis,” (4) “Keratins as Determinant of Health and Disease,” (5) “Identity, Characterization, and Application of Skin Stem Cells,” and (6) “Transplantation, Immunosuppression, and Tolerance.” The sessions were organized around the goal of this 60th Anniversary Meeting: to showcase the important research and medical breakthroughs that were first discovered in skin.
      In addition to the invited speakers, several people were selected to give short talks based on abstract submissions. As in the previous years, the discussion after each talk was productive and lively.
      To open the symposium, the Program Chair, Stuart Yuspa (National Cancer Institute, NIH, Bethesda, MD), gave an introduction, that included pictures from the 1970s, in which he described his first meeting with William Montagna, the initiator of this long-running symposium. Margaret Kripke (University of Texas MD Anderson Cancer Center, Houston, TX) followed with the Keynote Talk, in which she presented a timeline denoting the origin and highlights of photoimmunology as a discipline. She pointed out that the skin is an immunologic organ that reacts to UV radiation by altering antigen-presenting cells to stimulate cytokine production. As skin cells maintain an intimate relationship with immunologic cells, superficial skin treatments can have profound systemic consequences.
      Stuart Yuspa started the first day of the meeting with a historical overview of the milestones in cancer research and discoveries regarding the skin. He began with the description of occupational skin cancer in chimney sweeps in the 1770s. The next finding did not occur until the early 1900s, when coal tar and UV were discovered to cause skin cancer. Experiments using synthetic carcinogens conducted in the 1940s–1960s led to several discoveries, including the role of DNA repair, the ras oncogene, and the p53 tumor-suppressor gene in skin cancer, culminating with the development of new therapies in the 2000s.
      The goal of the first session, entitled “Seminal Discoveries in Cancer Biology: DNA Repair,” was to describe the role of DNA repair defects in skin cancer. Kenneth Kraemer (National Cancer Institute, NIH, Bethesda, MD) provided a historical overview of xeroderma pigmentosum, including Kaposi’s first clinical description in 1874 of the skin abnormalities, which is still relevant today. He discussed how the cause of xeroderma pigmentosum was determined in 1968 to be a DNA excision repair defect. More recently he discovered that primary melanomas from xeroderma pigmentosum patients had UV-type mutations in the PTEN tumor suppressor gene. DNA extracted from metastatic melanoma tissue blocks obtained in the autopsy of a xeroderma pigmentosum patient in 1971 had multiple PTEN mutations. He advised everyone to never discard tissue samples as they might be useful in the future. Laura Niedernhofer (University of Pittsburgh, Pittsburgh, PA) discussed why correct DNA repair is so critical to preventing cancer (hyperproliferation), neurologic degeneration, and premature aging (loss of regenerative capacity). Every day, cells accumulate many DNA lesions, including oxidative damage, per day, which must be repaired. If the damaged DNA is not repaired and is replicated, the cells may become cancerous. Unrepaired DNA damage may lead to increased cell death or abnormal transcription, resulting in premature aging. Qingyi Wei (University of Texas MD Anderson Cancer Center, Houston, TX) explained his molecular epidemiological studies of the role of polymorphisms in DNA repair genes in cancer risk in different populations. He measured DNA repair capacity using a host-cell reactivation assay of DNA repair that can be performed on cultured blood samples from large numbers of subjects. He found that the DNA repair phenotype and genotype can contribute to cancer susceptibility in the general population. Amanda McCullough (Oregon Health & Science University, Portland, OR) ended the session by discussing new strategies for cancer prevention involving the use of liposomal and TAT systems to introduce viral and bacteriophage DNA repair enzymes (pyrimidine dimer-specific DNA glycosylates) into living cells to increase their DNA repair capacity.
      Andrzej Dlugosz (University of Michigan, Ann Arbor, MI) began the second session, “Seminal Discoveries in Cancer Biology: Hedgehog Signaling,” with an overview of Hedgehog signaling via the receptor Patched, the signaling effector Smoothened, and the Gli family of transcription factors. In normal tissues, signaling activity is reversible and is dependent on the presence of Hedgehog ligand. However, in basal cell carcinoma (BCC), the Hedgehog pathway is constitutively active due to mutations in Patched or Smoothened, resulting in high levels of Gli transcriptional activity. On the basis of studies using several mouse models targeting GLI2* at different cell populations in the skin, the development of BCC subtypes and BCC-like tumors is defined by the cell of origin, the stage of the hair growth cycle, and the level of Hedgehog pathway activity. Anthony Oro (Stanford University, Palo Alto, CA) continued the discussion of the Hedgehog pathway by describing the structure of the primary cilium, an organelle found in most cell types that has a central role in coordinating Hedgehog pathway components to activate Gli proteins. MIM (missing in metastasis) is localized to the basal body, where it regulates the formation of cilia and Hedgehog responses. Protein kinase C iota/lambda (aPKC) and other proteins colocalize and form a complex with MIM at the basal body. aPKC inhibition reduces Sonic Hedgehog signaling and proliferation of the BCC cell line in vitro and BCC growth in mice, thus implicating aPKC as a potential new target for BCC treatment. Silvia Buonamici (Novartis Institutes for Biomedical Research, Cambridge, MA) described preclinical and clinical trial data using the Smoothened inhibitor LDE225, which showed efficacy in patients against both BCC and the Hedgehog-driven brain tumor, medulloblastoma, although disease progression was noted later on. Resistance in mouse models was linked to mutations in Smoothened, amplification of GLI2, or upregulation of phosphoinositide 3-kinase (PI3K) signaling. Use of a Smoothened antagonist and PI3K inhibitor delays the development of resistance, arguing for the use of combination therapy in future trials.
      Ervin Epstein (Children’s Hospital Oakland Research Institute, Oakland, CA) described a Gorlin syndrome BCC treatment using a different Hedgehog inhibitor, GDC-0449. This chemoprevention trial showed almost complete suppression of new tumor development in patients treated with the drug and remarkable regression of preexisting tumors. In contrast to earlier BCC trials in patients with advanced or metastatic tumors where drug resistance developed, resistance was not apparent in this trial. However, in patients who stop taking the drug, BCCs begin to grow again, suggesting that dormant tumor cells may persist despite a sizeable reduction in tumor mass. Studies defining the role of Hedgehog signaling in BCC development and maintenance may have far-reaching implications in oncology, as multiple internal cancers are also linked to deregulated Hedgehog signaling.
      The first speaker in the third session, “Seminal Discoveries in Cancer Biology: Signal Transduction and Cancer Pathogenesis,” was Stuart Yuspa, who discussed the effects of IL-1α signaling on the ras oncogene. Autocrine loops involving IL-1α, CXCR2 ligands, and NF-κB signaling result in oncogene-driven inflammation and angiogenesis. This theme was continued by Mitchell Denning (Loyola University School of Medicine, Maywood, IL), who discussed the activation of protein kinase C δ as a requirement to initiate the G2/M cell cycle checkpoint and suppress tumor formation. Sarah-Jane Cozzi (LEO Pharma, Inc., Newstead, Queensland, Australia) described the ingenol mebutate field treatment for UVB-damaged skin and how it removes p53 mutant patches and reduces squamous cell carcinoma (SCC) formation.
      Next were four short talks chosen from submitted abstracts. Frank de Gruijl (Leiden University Medical Center, Leiden, The Netherlands) explained that UV overexposure depletes p53 patches because it ablates the epidermal basal cell layer and thus resets the carcinoma timeline. Wendy Weinberg (Center for Drug Evaluation and Research, FDA, Bethesda, MD) reported that overexpression of Δp63α increases expression of the c-Rel subunit of NF-κB. Blocking this restores calcium growth arrest. Using an inducible K15-cre system and triple-crossed SMAD knockout and activated ras mice, Ruth White (Oregon Health & Science University, Portland, OR), a Farber Award winner, showed that microRNA-9 regulates cell migration and invasion in SCC. Christine Ho (University of California Berkeley, Oakland, CA), another Farber awardee, used statistical methods to determine the order of mutations in the induction of cancer. This may provide insights into cancer treatment and prevention.
      The next morning, Pierre Coulombe (Johns Hopkins University School of Medicine, Baltimore, MD) opened the fourth session, “Keratins as Determinant of Health and Disease,” with a timeline of publications, beginning in 1953 with James Watson and Francis Crick. Seminal papers by Werner Franke and Peter Steinert were published in the 1970s. The number of papers on keratin research spiked in the 1980s with the discovery of associated proteins, the sequences of K5 and K14, and their use as cassettes for expression. This led to the discovery that mutations in K5 and K14 caused epidermolysis bullosa simplex (EBS). Dr Coulombe continued with the new finding that K5 and K14 form a basket around the nucleus, which regulates its shape. Angela Christiano (Columbia University, New York, NY) described her work in using genomics to find new disease genes associated with hair defects. Next followed two short talks chosen from submitted abstracts: Maria Morasso (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD) explained that it is not clear which signal comes first in skin development, loss of the periderm, or formation of the epidermal barrier. Richard Wang (University of Texas Southwestern Medical Center, Dallas, TX), a Farber Award winner, explained how loss of K10 results in autophagy and that this is mediated via akt and beclin-1 phosphorylation. Thomas Magin (Translational Centre for Regenerative Medicine, Leipzig, Germany) tied together keratins, the barrier, and immunity in skin by showing that loss of K1 mediates IL-8 secretion, which affects the integrity of the cornified envelope. He ended by posing the question do K1 mutations predispose patients to inflammatory disorders?
      Sancy Leachman (University of Utah, Salt Lake City, UT) described the beneficial results of a new treatment for pachyonychia congenital in which a small interfering RNA that targets the K6a mutation is injected into the calluses of patients. Kathleen Green (Northwestern University Medical School, Chicago, IL) explained that cell–cell adhesion molecules were more than mere glue. Desmogleins are found everywhere in the cell and regulate differentiation without their adhesion domains.
      Two short talks chosen from the submitted abstracts followed. Holger Schluter (Peter MacCallum Cancer Center, Melbourne, Australia) showed that the WNT inhibitory factor WIF-1 regulates epidermal cell differentiation by inducing G1 arrest. Arup Indra (Oregon State University, Corvallis, OR) discussed the requirement for CTIP2 (COUP-TF-interacting protein 2) to maintain Notch1 levels in basal cells in order to regulate early differentiation. Tom Misteli (National Cancer Institute, NIH, Bethesda, MD) ended this session with a general description of the nuclear intermediate filaments, the lamins, and how a point mutation causes progeria, a rare genetic condition that causes rapid aging in children. Currently the treatment is anti-formyl transferase drugs, but they work for only a short time. He is presently working on a small molecule to target the causal lamin mutation.
      Fiona Watt (Cancer Research UK London Research Institute, London, UK) began the fifth session, “Identity, Characterization, and Application of Skin Stem Cells” with a history of epidermal stem cells and noted that the important question of whether the stem cell is hard wired or a response to external stimuli remains unanswered. She discussed the WNT pathway and how cross-talk between stem cells and mesenchymal cells results in hair follicle formation and maintenance. She reported that as few as 3% of the viable dermal papilla cells are sufficient to form a hair follicle. Yann Barrandon (Ecole Polytechnique Federale de Lausanne, Switzerland) continued with a discussion of stem cells’ microenvironment and stated that it is still unknown whether tissue stem cells have memory or whether their fate is determined by their microenvironment.
      Two short talks chosen from the abstracts followed. Ying Xiao (National Cancer Institute, NIH, Bethesda, MD) claimed to have found vessels associated with label-retaining cells, suggesting a perivascular reservoir of stem cells. Krysztof Kobielak (University of Southern California, Los Angeles, CA) described the integration of the BMP and WNT signaling pathways in forming hair follicles. Dennis Roop (University of Colorado, Aurora, CO) described his work using induced pluripotent stem cells to correct the genetic defect in EBS. Jakob Tolar (University of Minnesota, Minneapolis, MN) followed by describing his success of using bone marrow stem cells to increase collagen type VII and laminin 5 production in patients with recessive dystrophic epidermolysis bullosa (EB) and junctional EB, respectively. He posed two unanswered questions: Which bone marrow cells home to the skin? Which skin niche do they go to? Yosef Refaeli (University of Colorado, Aurora, CO) described his method of using TAT-myc transfection to produce a bone marrow stem cell line that can be transplanted across allogeneic barriers without producing graft-versus-host disease.
      Next were two short talks chosen from the submitted abstracts. First, Petra Boukamp (German Cancer Research Center, Heidelberg, Germany) discussed how overexpression of SMAD 7 induces differentiation rather than quiescence in stem cells. Second, Ian Mackenzie (Queen Mary, University of London, UK) explained how SCC cancer stem cells can switch back and forth from nonmotile epithelial cells to motile mesenchymal cells and that switching drug treatments is thus necessary in order to have an impact on all SCC cells. Michele De Luca (University of Modena and Reggio Emilia, Modena, Italy) ended this session with an exciting description of how using only 3000 limbal stem cells (3% of the total population) mixed with stromal cells is sufficient to permanently regenerate the corneal epithelium in patients who have suffered chemical burns or infections. Moreover, this requires only 1mm of limbus from an unaffected eye. Thus, he is currently restoring the sight of patients who have lost over 95% of their limbal tissue.
      The last session, “Transplantation, Immunosuppression, and Tolerance,” was chaired by Stephen Katz (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD), who gave an overview of adaptive immunity, including the fact that skin is the most difficult tissue to adoptively transplant as an allograft. Kathryn Wood (University of Oxford, Oxford, UK) presented a proof of concept that it is regulatory T lymphocytes that control or prevent human skin allograft rejection.
      Two short talks chosen from the submitted abstracts followed. Richard Presland (University of Washington, Seattle, WA) described the use of proteomics in saliva samples to detect potential graft-versus-host disease. Jane Yoo (University of Washington, Seattle, WA) explained that 10% of the T lymphocytes in the skin are regulatory T cells, and that the early activation of these cells modulates local IL-2 signaling, making the skin more contact sensitive. Stephen Katz followed with a description of a mouse model in which self-peptides are used to block the autoreactivity of cytolytic T cells, resulting in mice that develop systemic tolerance. He also discussed the experience with and future prospects of using self-peptides to induce tolerance in humans. Sarah Arron (University of California, San Francisco, CA) found that, even with the use of several advanced molecular biological methodologies, there was no evidence that human papilloma virus is frequently present in SCCs. This contradicts popular belief. Shay Soker (Wake Forest University, Winston-Salem, NC) described new methods using the extracellular matrix on scaffolds to bioengineer whole organs from patients’ cells for transplant.
      Allan Balmain (University of California, San Francisco, CA) ended the session with a keynote talk about the future. He discussed how to build a genetic network from a small piece of skin using computation to find the correlations of genes with the same scheme to make a complete network. Thus, in the near future, we will be able to answer specific questions about specific genes in normal tissues or in diseases.

      2011 SID Eugene M. Farber Travel Awards for Young Investigators

      As in the past, nine young investigators attended the Montagna Symposium thanks to a generous donation from the Eugene M. Farber family through the Society for Investigative Dermatology.
      Janina Baer, PhD
      Candidate, Developmental Biology Department, University of Leipzig
      Christine Ho, PhD
      Candidate, Department of Statistics, University of California, Berkeley
      Rajan Kulkarni, MD/PhD
      Resident, Department of Dermatology, University of California, Los Angeles
      Marco Leung, PhD
      Candidate, Graduate School of Biomedical Sciences, Department of Immunology, University of Texas MD Anderson Center
      Anjali Mishra, MD/PhD
      Postdoctoral Researcher, Hematology and Oncology, The Ohio State University
      Heuijoon Park, PhD
      Postdoctoral Fellow, Laboratory of Stem Cells and Cancer, The Hormel Institute, University of Minnesota
      Padmakumar Velayuthan Chellammal, PhD
      Research Fellow, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH
      Richard Wang, MD/PhD
      Instructor, Department of Dermatology, University of Texas Southwestern Medical Center
      Ruth White, PhD, MD
      Candidate, Oregon Health & Science University School of Medicine

      Director’s Award

      (additional funds from Mrs Ruth Farber in memory of Dr Eugene Farber)
      LaTondra Lawrence, PhD
      Candidate, Texas Women’s University
      Montagna 2012
      “Keeping It All Together: Adhesion, the Cytoskeleton, and Signaling in Morphogenesis and Tissue Function”
      11–15 October 2012, Salishan Resort, Gleneden Beach, Oregon
      Program Chairs:
      Kathleen J. Green, PhD
      Departments of Pathology and Dermatology and the R.H. Lurie Cancer Center,
      Northwestern University Feinberg School of Medicine, Chicago, Illinois
      Masayuki Amagai, MD/PhD
      Department of Dermatology, Keio University, Tokyo, Japan

      ACKNOWLEDGMENTS

      • National Institute of Arthritis and Musculoskeletal and Skin Diseases (5 R13 AR009431-46)
      • The Eugene M. Farber family
      • Oregon Health & Science University Department of Dermatology
      • Epidermolysis Bullosa Medical Research Foundation; Allergan Biosciences; Genentech Inc.; Johnson & Johnson Consumer & Personal Products Worldwide; Lilly, USA, LLC; The Proctor & Gamble Company; Amgen, Inc.; OHSU Knight Cancer Institute; Curtis Thompson, MD & Associates; Orentreich Family Foundation; Sigma-Aldrich Co. LLC; Drs Jim and Diane Baker; Dr Lorraine Kligman.