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    Stephen R Lyle MD, PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-4774
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentPathology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

        Overview 
        Narrative

        Stephen Lyle earned his B.A. and M.S. in Biology and Biochemistry from the University of Chicago in 1988. He completed the M.D./Ph.D., program at the University of Chicago Medical School in 1995. From 1995-99, Dr. Lyle was an Anatomic Pathology resident at The University of Pennsylvania Hospital, and also conducted post-doctoral research in the Department of Dermatology. He then completed the 1-year fellowship in Dermatopathology at Harvard Medical School before joining the faculty at Beth Israel Deaconess Medical Center. He was an assistant professor of pathology and associate director of the Dermatopathology Fellowship at Harvard until 2005 when he became a member of the UMass Cancer Biology faculty and Director of the UMass Cancer Center Tissue Bank.

        Adult Epithelial Stem CellsSteveLyle

        Research in the Lyle laboratory focuses on the molecular and cellular characterization of adult epithelial stem cells and pathways which lead to cancer from stem cells. We have identified a number of differentially expressed genes within the stem cell compartment and we are investigating the functions of these genes in mediating stem cell properties such as self-renewal, growth, differentiation, adhesion and migration. The goals are to characterize genes which define the stem cell phenotype and identify critical pathways that mediate stem cell behavior and function. We are also addressing two important questions regarding stem cells and cancer; 1) do cancers arise from adult stem cells, and if so, what are the molecular mechanisms which transform a stem cell?, and 2) do cancers themselves have stem cells, termed “cancer stem cells”, which are responsible for tumor growth, recurrence and metastasis?

        Lab Projects

        Stem Cell Genes

        Building on our earlier identification of the skin stem cell niche and the discovery of the keratin 15 stem cell marker (Lyle et al., J Cell Sci. 1998;111, 3179-88), we have been interested in characterizing other functional genes within stem cells. In a screen of differentially expressed genes, we identified a number of genes which are up-regulated in stem cells. One of the genes we have been studying, the dual-specificity kinase CLK1, shows striking co-expression in the stem cell compartment (Figure 1). Using a number of in vitro assays of stem cell behavior, we are investigating the role of CLK1 in mediating the stem cell phenotype. In addition, to CLK1, other known differentially expressed genes are beginning to be examined.

        Unique Stem Cell Factor

        Earlier we showed that the stem cells of skin resided in a specific area of the hair follicle called the "bulge". We and others have shown that these cells have stem cell properties of self-renewal, slow-cycling and multi-potentiality within skin, giving rise to epidermis, sebaceous gland and hair follicle. These cells are responsible for regeneration of the hair follicle during hair cycling. Subtraction hybridization experiments have been performed to compare the adult epithelial stem cells of the hair follicle bulge to the non-stem cell compartment. One unique sequence, which has homology to a vitamin D regulated protein, has been selected for further investigation. This transcript has been confirmed to be over-expressed in the stem cell by real-time PCR and immunofluorescence. We are currently characterizing the biochemical properties and functional significance of this unique protein within stem cells, using a retroviral and adenoviral transfection approach.

        Molecular Pathogenesis of Tumors from Stem Cells

        One of our main goals to understand fate determination of adult epithelial stem cells and alterations in stem cells which lead to tumor formation. Characterizing normal and abnormal pathways of stem cell growth and differentiation is critical for understanding the cellular basis for oncogenesis and for the development of novel approaches to cancer prevention, detection, diagnosis and therapy. The major hypothesis that will be tested in this proposal is that alterations in stem cell fate and growth play a role in tumorigenesis. Epithelial stem cells have a life-span at least as long as that of the organism, and thus they are thought to be susceptible to multiple genetic “hits” which cumulatively may result in tumor formation. In hereditary cancers, one somatic mutation is inherited, leading to increased frequency of two hits and tumor formation. One example is the Muir-Torre syndrome, a familial association of cutaneous sebaceous neoplasia with internal malignancy (mostly colon cancer), caused by mismatch repair defects and microsatellite instability (MSI). We previously showed that human sebaceous skin tumors, both sporadic and from Muir-Torre patients, had a similar immunophenotype to experimentally derived mouse tumors carrying the DNLef1 transgene (Niemann et al, 2003). Since Lef/Tcf genes can be targets of MSI in colon cancers, we hypothesize that Lef/Tcf mutations are also involved the pathogenesis of human sebaceous tumors, analogous to the transgenic mouse. Because earlier work also implicated the hedgehog signaling pathway in sebaceous tumors, we will more closely examine molecular changes in this and other oncogenic pathways. Based on our earlier identification of epithelial stem cells in human skin (Lyle et al, 1998), we have developed methods to isolate and culture these cells, which maintain stem cell properties in vitro. We will now utilize these cells to examine the significance of Lef/Tcf mutations in modifying growth and fate determination of adult epithelial stem cells.



        Rotation Projects

        Rotation projects are designed to expose students to the biology of adult stem cells, the mechanisms of tumorigenesis and to provide them with an appreciation for translational cancer research. These projects are focused on the major themes of the lab, which are:

        1. Understanding the relative effects of oncogenic mutations on stem cells compared to the non-stem cell population from adult human skin. A key component of this project is to evaluate the Beta-catenin/Lef-1 signaling pathway on cultured epithelial stem cells and non-stem cells.

        2. Studying the function of differently expressed genes in mediating stem cell behavior. The goal of this project is to understand the molecular mechanisms which control the critical properties of stem cell self-renewal, proliferation, adhesion and migration.

        3. Identifying, isolating and characterizing “cancer stem cells” from human and mouse model tumors. Cancers are thought to possess a sub-population of slowly-cycling cancer stem cells which are responsible for tumor growth, recurrence and metastasis. The goal of this project is to begin to characterize these cells to help better target them therapeutically.

        The goal for all of these projects is to use the data obtained to help understand human tumorigenesis at the molecular, cellular and tissue levels, and be able to devise better treatments.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Goel HL, Chang C, Pursell B, Leav I, Lyle S, Xi HS, Hsieh CC, Adisetiyo H, Roy-Burman P, Coleman IM, Nelson PS, Vessella RL, Davis RJ, Plymate SR, Mercurio AM. VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer. Cancer Discov. 2012 Oct; 2(10):906-921.
          View in: PubMed
        2. Zembowicz A, Yang SE, Kafanas A, Lyle SR. Correlation between histologic assessment and fluorescence in situ hybridization using MelanoSITE in evaluation of histologically ambiguous melanocytic lesions. Arch Pathol Lab Med. 2012 Dec; 136(12):1571-9.
          View in: PubMed
        3. Shalin SC, Sakharpe A, Lyle S, Lev D, Calonje E, Lazar AJ. p53 staining correlates with tumor type and location in sebaceous neoplasms. Am J Dermatopathol. 2012 Apr; 34(2):129-35; quiz 136-8.
          View in: PubMed
        4. Zembowicz A, Navarro P, Walters S, Lyle SR, Moschella SL, Miller D. Subcutaneous thrombotic vasculopathy syndrome: an ominous condition reminiscent of calciphylaxis: calciphylaxis sine calcifications? Am J Dermatopathol. 2011 Dec; 33(8):796-802.
          View in: PubMed
        5. Moore N, Houghton J, Lyle S. Slow-cycling therapy-resistant cancer cells. Stem Cells Dev. 2012 Jul 1; 21(10):1822-30.
          View in: PubMed
        6. Kashyap T, Germain E, Roche M, Lyle S, Rabinovitz I. Role of ß4 integrin phosphorylation in human invasive squamous cell carcinoma: regulation of hemidesmosome stability modulates cell migration. Lab Invest. 2011 Oct; 91(10):1414-26.
          View in: PubMed
        7. Al-Zaid T, Vanderweil S, Zembowicz A, Lyle S. Sebaceous gland loss and inflammation in scarring alopecia: A potential role in pathogenesis. J Am Acad Dermatol. 2011 Sep; 65(3):597-603.
          View in: PubMed
        8. Guo Z, Draheim K, Lyle S. Isolation and culture of adult epithelial stem cells from human skin. J Vis Exp. 2011; (49).
          View in: PubMed
        9. Zembowicz A, Ahmad A, Lyle SR. A comprehensive analysis of a web-based dermatopathology second opinion consultation practice. Arch Pathol Lab Med. 2011 Mar; 135(3):379-83.
          View in: PubMed
        10. Gannon HS, Donehower LA, Lyle S, Jones SN. Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin. Dev Biol. 2011 May 1; 353(1):1-9.
          View in: PubMed
        11. Draheim KM, Lyle S. Epithelial stem cells. Methods Mol Biol. 2011; 750:261-74.
          View in: PubMed
        12. Hutchinson L, Stenstrom B, Chen D, Piperdi B, Levey S, Lyle S, Wang TC, Houghton J. Human Barrett's Adenocarcinoma of the Esophagus, Associated Myofibroblasts, and Endothelium Can Arise from Bone Marrow-Derived Cells After Allogeneic Stem Cell Transplant. Stem Cells Dev. 2011 Jan; 20(1):11-7.
          View in: PubMed
        13. Moore N, Lyle S. Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J Oncol. 2011; 2011.
          View in: PubMed
        14. Straza MW, Paliwal S, Kovi RC, Rajeshkumar B, Trenh P, Parker D, Whalen GF, Lyle S, Schiffer CA, Grossman SR. Therapeutic targeting of C-terminal binding protein in human cancer. Cell Cycle. 2010 Sep; 9(18):3740-50.
          View in: PubMed
        15. Houghton J, Li H, Fan X, Liu Y, Liu JH, Rao VP, Poutahidis T, Taylor CL, Jackson EA, Hewes C, Lyle S, Cerny A, Bowen G, Cerny J, Moore N, Kurt-Jones EA, Erdman SE. Mutations in bone marrow-derived stromal stem cells unmask latent malignancy. Stem Cells Dev. 2010 Aug; 19(8):1153-66.
          View in: PubMed
        16. Haince JF, Houde M, Beaudry G, L'espérance S, Garon G, Desaulniers M, Hafer LJ, Heald JI, Lyle S, Grossman SR, Têtu B, Sargent DJ, Fradet Y. Comparison of histopathology and RT-qPCR amplification of guanylyl cyclase C for detection of colon cancer metastases in lymph nodes. J Clin Pathol. 2010 Jun; 63(6):530-7.
          View in: PubMed
        17. Li H, Fan X, Stoicov C, Liu JH, Zubair S, Tsai E, Ste Marie R, Wang TC, Lyle S, Kurt-Jones E, Houghton J. Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver. Gastroenterology. 2009 Sep; 137(3):934-44, 944.e1-4.
          View in: PubMed
        18. Pozdnyakova O, Grossman J, Barbagallo B, Lyle S. The hair follicle barrier to involvement by malignant melanoma. Cancer. 2009 Mar 15; 115(6):1267-75.
          View in: PubMed
        19. Mudhasani R, Zhu Z, Hutvagner G, Eischen CM, Lyle S, Hall LL, Lawrence JB, Imbalzano AN, Jones SN. Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J Cell Biol. 2008 Jun 30; 181(7):1055-63.
          View in: PubMed
        20. Roh C, Roche M, Guo Z, Photopoulos C, Tao Q, Lyle S. Multi-potentiality of a new immortalized epithelial stem cell line derived from human hair follicles. In Vitro Cell Dev Biol Anim. 2008 Jul-Aug; 44(7):236-44.
          View in: PubMed
        21. Lo Celso C, Berta MA, Braun KM, Frye M, Lyle S, Zouboulis CC, Watt FM. Characterization of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-Myc and beta-catenin. Stem Cells. 2008 May; 26(5):1241-52.
          View in: PubMed
        22. Grossman SR, Lyle S, Resnick MB, Sabo E, Lis RT, Rosinha E, Liu Q, Hsieh CC, Bhat G, Frackelton AR, Hafer LJ. p66 Shc tumor levels show a strong prognostic correlation with disease outcome in stage IIA colon cancer. Clin Cancer Res. 2007 Oct 1; 13(19):5798-804.
          View in: PubMed
        23. Chhibber V, Lyle S, Mahalingam M. Ductal eccrine carcinoma with squamous differentiation: apropos a case. J Cutan Pathol. 2007 Jun; 34(6):503-7.
          View in: PubMed
        24. Ivan D, Nash JW, Prieto VG, Calonje E, Lyle S, Diwan AH, Lazar AJ. Use of p63 expression in distinguishing primary and metastatic cutaneous adnexal neoplasms from metastatic adenocarcinoma to skin. J Cutan Pathol. 2007 Jun; 34(6):474-80.
          View in: PubMed
        25. Kazantseva A, Goltsov A, Zinchenko R, Grigorenko AP, Abrukova AV, Moliaka YK, Kirillov AG, Guo Z, Lyle S, Ginter EK, Rogaev EI. Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH. Science. 2006 Nov 10; 314(5801):982-5.
          View in: PubMed
        26. Roh C, Lyle S. Cutaneous stem cells and wound healing. Pediatr Res. 2006 Apr; 59(4 Pt 2):100R-3R.
          View in: PubMed
        27. Lipscomb EA, Simpson KJ, Lyle SR, Ring JE, Dugan AS, Mercurio AM. The alpha6beta4 integrin maintains the survival of human breast carcinoma cells in vivo. Cancer Res. 2005 Dec 1; 65(23):10970-6.
          View in: PubMed
        28. Roh C, Tao Q, Photopoulos C, Lyle S. In vitro differences between keratinocyte stem cells and transit-amplifying cells of the human hair follicle. J Invest Dermatol. 2005 Dec; 125(6):1099-105.
          View in: PubMed
        29. Roh C, Tao Q, Lyle S. Dermal papilla-induced hair differentiation of adult epithelial stem cells from human skin. Physiol Genomics. 2004 Oct 4; 19(2):207-17.
          View in: PubMed
        30. Liu Y, Lyle S, Yang Z, Cotsarelis G. Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J Invest Dermatol. 2003 Nov; 121(5):963-8.
          View in: PubMed
        31. Ruvinsky I, Chertkov O, Borue XV, Agulnik SI, Gibson-Brown JJ, Lyle SR, Silver LM. Genetics analysis of mouse mutations Abnormal feet and tail and rough coat, which cause developmental abnormalities and alopecia. Mamm Genome. 2002 Dec; 13(12):675-9.
          View in: PubMed
        32. Pantanowitz L, Lyle S, Tahan SR. Fibroadenoma of the eyelid. Am J Dermatopathol. 2002 Jun; 24(3):225-9.
          View in: PubMed
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