University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Dean Sheppard, MD

Dean Sheppard, MD

Professor, Department of Medicine, UCSF

Cancer Center Program Memberships

Non-aligned

Research Summary

Dean Sheppard is a Professor of Medicine, Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep and director of the Lung Biology Center. His research focuses on the in vivo functions of integrins and the molecular mechanisms underlying pulmonary (and other organ) fibrosis. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common lung diseases. Utilizing mice with global or conditional knockouts of the epithelial-restricted integrin, avß6, and the widely expressed integrins, a5ß1, a9ß1, avß5 and avß8, the lab has identified important roles for these integrins in models of each common lung disease and key steps upstream and downstream of the integrins that provide potential therapeutic targets. His lab identified the unique roles that 3 integrins, avß1, avß6 and avß8 play in activation of the growth factor, latent transforming growth factor beta (TGFß) and has identified critical roles for this process in acute lung injury, pulmonary fibrosis, post-natal brain development and immunosuppression in the setting of cancer. The lab has partnered with academic colleagues, biotech and pharmaceutical companies to develop novel antibody and small molecule inhibitors of these integrins that are in various stages of pre-clinical and clinical development. Current work is also using single cell RNA sequencing to understand the heterogeneity of cells that contribute to tissue fibrosis and cancer, and exploring the potential of engineering circulating cells for local delivery of novel therapeutics to fibrotic organs and tumors.

Education

Harvard College, Cambridge, MA, A.B., 1972
SUNY at Stony Brook, Stony Brook, NY, M.D., 1975, Medicine
Univ of Washington, Seattle, WA, Resident, 1975-78, Internal Medicine
Univ of California, San Francisco, San Francisco, Fellow, 1978-80, Pulmonary

Honors & Awards

  • 1992
    Elected Member, American Society for Clinical Investigation
  • 1995
    Elected Member, Association of American Physicians
  • 1995
    Clean Air Award, California Lung Association
  • 1998
    Scientific Achievement Award, American Thoracic Society
  • 2004-2014
    NIH Merit Award
  • 2013
    Top 20 Translational Scientists, Nature Biotechnology
  • 2016
    UCSF Fraculty Research Lecture in Translational Science
  • 2017
    elected to American Academy of Arts and Sciences

Selected Publications

  1. Cassandras M, Wang C, Kathiriya J, Tsukui T, Matatia P, Matthay M, Wolters P, Molofsky A, Sheppard D, Chapman H, Peng T. Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung. Nat Cell Biol. 2020 Oct 12.
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  2. Sundaram A, Chen C, Isik Reed N, Liu S, Ki Yeon S, McIntosh J, Tang YZ, Yang H, Adler M, Beresis R, Seiple IB, Sheppard D, DeGrado WF, Jo H. Dual antagonists of a5ß1/ avß1 integrin for airway hyperresponsiveness. Bioorg Med Chem Lett. 2020 Sep 29; 127578.
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  3. Wong JC, Perez-Mancera PA, Huang TQ, Kim J, Grego-Bessa J, Alzamora MDP, Kogan SC, Sharir A, Keefe SH, Morales CE, Schanze D, Castel P, Hirose K, Huang GN, Zenker M, Sheppard D, Klein O, Tuveson D, Braun BS, Shannon K. KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice. JCI Insight. 2020 Sep 29.
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  4. Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, Hu JK, Schaub JR, Ho SS, Rao V, Marlow MM, Turner SM, Sedki M, Pantano L, Ghoshal S, Ferreira DDS, Ma HY, Duwaerts CC, Espanol-Suner R, Wei L, Newcomb B, Mileva I, Canals D, Hannun YA, Chung RT, Mattis AN, Fuchs BC, Tager AM, Yimlamai D, Weaver VM, Mullen AC, Sheppard D, Chen JY. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci Transl Med. 2020 Aug 19; 12(557).
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  5. Santander N, Lizama CO, Meky E, McKinsey GL, Jung B, Sheppard D, Betsholtz C, Arnold TD. Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier. J Clin Invest. 2020 Aug 03; 130(8):4055-4068.
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  6. Tsukui T, Sun KH, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, Henderson NC, Adams TS, Schupp JC, Poli SD, Rosas IO, Kaminski N, Matthay MA, Wolters PJ, Sheppard D. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat Commun. 2020 04 21; 11(1):1920.
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  7. Zhang Z, Bai M, Barbosa GO, Chen A, Wei Y, Luo S, Wang X, Wang B, Tsukui T, Li H, Sheppard D, Kornberg TB, Ma DK. Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking. Sci Adv. 2020 02; 6(7):eaay7667.
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  8. Del Cid JS, Reed NI, Molnar K, Liu S, Dang B, Jensen SA, DeGrado W, Handford PA, Sheppard D, Sundaram AB. A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion. J Biol Chem. 2019 11 29; 294(48):18232-18243.
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  9. Arnold TD, Lizama CO, Cautivo KM, Santander N, Lin L, Qiu H, Huang EJ, Liu C, Mukouyama YS, Reichardt LF, Zovein AC, Sheppard D. Impaired aVß8 and TGFß signaling lead to microglial dysmaturation and neuromotor dysfunction. J Exp Med. 2019 04 01; 216(4):900-915.
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  10. Bengs S, Becker E, Busenhart P, Spalinger MR, Raselli T, Kasper S, Lang S, Atrott K, Mamie C, Vavricka SR, von Boehmer L, Knuth A, Tuomisto A, Mäkinen MJ, Hruz P, Turina M, Rickenbacher A, Petrowsky H, Weber A, Frei P, Halama M, Jenkins G, Sheppard D, Croner RS, Christoph J, Britzen-Laurent N, Naschberger E, Schellerer V, Stürzl M, Fried M, Rogler G, Scharl M. ß6 -integrin serves as a novel serum tumor marker for colorectal carcinoma. Int J Cancer. 2019 08 01; 145(3):678-685.
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  11. Bulek K, Chen X, Parron V, Sundaram A, Herjan T, Ouyang S, Liu C, Majors A, Zepp J, Gao J, Dongre A, Bodaszewska-Lubas M, Echard A, Aronica M, Carman J, Garantziotis S, Sheppard D, Li X. IL-17A Recruits Rab35 to IL-17R to Mediate PKCa-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility. J Immunol. 2019 03 01; 202(5):1540-1548.
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  12. Thamsen M, Ghosh R, Auyeung VC, Brumwell A, Chapman HA, Backes BJ, Perara G, Maly DJ, Sheppard D, Papa FR. Small molecule inhibition of IRE1a kinase/RNase has anti-fibrotic effects in the lung. PLoS One. 2019; 14(1):e0209824.
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  13. Greenhalgh SN, Matchett KP, Taylor RS, Huang K, Li JT, Saeteurn K, Donnelly MC, Simpson EEM, Pollack JL, Atakilit A, Simpson KJ, Maher JJ, Iredale JP, Sheppard D, Henderson NC. Loss of Integrin avß8 in Murine Hepatocytes Accelerates Liver Regeneration. Am J Pathol. 2019 02; 189(2):258-271.
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  14. Fong V, Hsu A, Wu E, Looney AP, Ganesan P, Ren X, Sheppard D, Wicher SA, Thompson MA, Britt RD, Prakash YS, Bhattacharya M. Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice. JCI Insight. 2018 11 02; 3(21).
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  15. Podolsky MJ, Gupta D, Ha A, Ta R, Khalifeh-Soltani A, McKleroy W, Datta R, Sheppard D, Atabai K. Cell division cycle 7 kinase is a negative regulator of cell-mediated collagen degradation. . 2018 09 01; 315(3):L360-L370.
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  16. Kim KK, Sheppard D, Chapman HA. TGF-ß1 Signaling and Tissue Fibrosis. Cold Spring Harb Perspect Biol. 2018 04 02; 10(4).
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  17. Stockis J, Liénart S, Colau D, Collignon A, Nishimura SL, Sheppard D, Coulie PG, Lucas S. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin aVß8. Proc Natl Acad Sci U S A. 2017 11 21; 114(47):E10161-E10168.
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  18. Tsujino K, Li JT, Tsukui T, Ren X, Bakiri L, Wagner E, Sheppard D. Fra-2 negatively regulates postnatal alveolar septation by modulating myofibroblast function. . 2017 Nov 01; 313(5):L878-L888.
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  19. Jenkins RG, Moore BB, Chambers RC, Eickelberg O, Königshoff M, Kolb M, Laurent GJ, Nanthakumar CB, Olman MA, Pardo A, Selman M, Sheppard D, Sime PJ, Tager AM, Tatler AL, Thannickal VJ, White ES. An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2017 05; 56(5):667-679.
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  20. Chang Y, Lau WL, Jo H, Tsujino K, Gewin L, Reed NI, Atakilit A, Nunes ACF, DeGrado WF, Sheppard D. Pharmacologic Blockade of avß1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo. J Am Soc Nephrol. 2017 Jul; 28(7):1998-2005.
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