University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Harold A. Chapman, MD

Harold A. Chapman, MD

Professor, Department of Medicine, UCSF

Cancer Center Program Memberships

Affiliate Member

Research Summary

The Chapman lab has had a longstanding interest and track record of innovation in the field of tissue remodeling, particularly as it relates to lung disease. For many years my work primarily focused on proteolytic enzymes. My group and I cloned and characterized several new members of the cathepsin family and elucidated their roles in bone, brain, lung, and immune disorders. I also pursued basic mechanisms by which proteases and adhesion receptors coordinate cell invasion and extracellular matrix remodeling and this has led to longstanding interest in integrin signaling. We were the first to recognize the physical and functional connections between integrins and the key cell surface protease, plasminogen activator. After moving from Harvard to UCSF 12 years ago I focused my lab on pulmonary fibrosis as a disorder of great unmet medical need and a logical extension of my prior work in matrix biology. I pioneered the in vivo investigation of the role of epithelial mesenchymal transition (EMT) in pulmonary fibrosis and uncovered mechanistic insight as to how integrins and hypoxia regulate epithelial cell plasticity. These studies have provided a roadmap for defining the role of EMT signaling in human fibrosis and lung cancer. More recently we have extended our studies of epithelial plasticity into the realm of lung stem/progenitor cells and are committed to defining the regenerative potential of the lung after injury.

I have trained approximately twenty PhD and/or MD post-docs who now populate academic departments and pharmaceutical labs. As a physician scientist myself, I have particularly enjoyed the responsibility of motivating and training capable young physicians for careers in disease-oriented research. These now include Division and Department Chairs as well as several independent medicine faculty with successful NIH-funded research programs. My lab now is comprised of mainly PhD trainees and junior faculty and we are committed to understanding and targeting the emerging relationship between hypoxia, EMT, and tissue remodeling during fibrogenesis and cancer progression.

Education

Tulane University, 1968, Premedical
University of Alabama School of Medicine, M.D., 1972, Medicine

Honors & Awards

  • 1972
    Alpha Omega Alpha, University of Alabama School of Medicine
  • 1985-1990
    Career Investigator Award, American Lung Association
  • 1987
    American Society for Clinical Investigation
  • 1998
    American Association of Physicians
  • 2001
    MERIT Award, NIH/NHLBI

Selected Publications

  1. Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, Wei Y, Chapman HA, Yamauchi M, Behrens C, Raso G, Soto LMS, Cuentes ERP, Wistuba II, Kurie JM, Gibbons DL. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nat Commun. 2020 09 09; 11(1):4520.
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  2. Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I, Mayr CH, Tsidiridis G, Lange M, Mattner LF, Yee M, Ogar P, Sengupta A, Kukhtevich I, Schneider R, Zhao Z, Voss C, Stoeger T, Neumann JHL, Hilgendorff A, Behr J, O'Reilly M, Lehmann M, Burgstaller G, Königshoff M, Chapman HA, Theis FJ, Schiller HB. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat Commun. 2020 07 16; 11(1):3559.
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  3. Chapman HA, Wei Y, Montas G, Leong D, Golden JA, Trinh BN, Wolters PJ, Le Saux CJ, Jones KD, Hills NK, Foster E, Oldham JM, Linderholm AL, Kotak P, Decaris M, Turner S, Song JW. Reversal of TGFß1-Driven Profibrotic State in Patients with Pulmonary Fibrosis. N Engl J Med. 2020 03 12; 382(11):1068-1070.
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  4. Kathiriya JJ, Chapman HA. VEGF Drives the Car toward Better Gas Exchange. Dev Cell. 2020 Mar 09; 52(5):546-547.
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  5. Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA. Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration. Cell Stem Cell. 2020 03 05; 26(3):346-358.e4.
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  6. Wiley CD, Brumwell AN, Davis SS, Jackson JR, Valdovinos A, Calhoun C, Alimirah F, Castellanos CA, Ruan R, Wei Y, Chapman HA, Ramanathan A, Campisi J, Jourdan Le Saux C. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI Insight. 2019 12 19; 4(24).
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  7. LaCanna R, Liccardo D, Zhang P, Tragesser L, Wang Y, Cao T, Chapman HA, Morrisey EE, Shen H, Koch WJ, Kosmider B, Wolfson MR, Tian Y. Yap/Taz regulate alveolar regeneration and resolution of lung inflammation. J Clin Invest. 2019 04 15; 129(5):2107-2122.
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  8. 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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  9. Le Saux CJ, Chapman HA. Idiopathic Pulmonary Fibrosis: Cell Death and Inflammation Revisited. Am J Respir Cell Mol Biol. 2018 08; 59(2):137-138.
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  10. Wang C, de Mochel NSR, Christenson SA, Cassandras M, Moon R, Brumwell AN, Byrnes LE, Li A, Yokosaki Y, Shan P, Sneddon JB, Jablons D, Lee PJ, Matthay MA, Chapman HA, Peng T. Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. J Clin Invest. 2018 10 01; 128(10):4343-4358.
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  11. 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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  12. Zhou Y, Horowitz JC, Naba A, Ambalavanan N, Atabai K, Balestrini J, Bitterman PB, Corley RA, Ding BS, Engler AJ, Hansen KC, Hagood JS, Kheradmand F, Lin QS, Neptune E, Niklason L, Ortiz LA, Parks WC, Tschumperlin DJ, White ES, Chapman HA, Thannickal VJ. Extracellular matrix in lung development, homeostasis and disease. Matrix Biol. 2018 11; 73:77-104.
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  13. Wei Y, Kim TJ, Peng DH, Duan D, Gibbons DL, Yamauchi M, Jackson JR, Le Saux CJ, Calhoun C, Peters J, Derynck R, Backes BJ, Chapman HA. Fibroblast-specific inhibition of TGF-ß1 signaling attenuates lung and tumor fibrosis. J Clin Invest. 2017 Oct 02; 127(10):3675-3688.
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  14. Xi Y, Kim T, Brumwell AN, Driver IH, Wei Y, Tan V, Jackson JR, Xu J, Lee DK, Gotts JE, Matthay MA, Shannon JM, Chapman HA, Vaughan AE. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol. 2017 Aug; 19(8):904-914.
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  15. McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP, Ahmad A, Riches DWH, Chapman HA, Mason RJ, Tuder RM, Zemans RL. Hypoxia-Inducible Factor 1a Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury. Am J Pathol. 2017 Aug; 187(8):1772-1786.
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  16. Vaughan AE, Chapman HA. Failure of Alveolar Type 2 Cell Maintenance Links Neonatal Distress with Adult Lung Disease. Am J Respir Cell Mol Biol. 2017 04; 56(4):415-416.
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  17. Kanegai CM, Xi Y, Donne ML, Gotts JE, Driver IH, Amidzic G, Lechner AJ, Jones KD, Vaughan AE, Chapman HA, Rock JR. Persistent Pathology in Influenza-Infected Mouse Lungs. Am J Respir Cell Mol Biol. 2016 10; 55(4):613-615.
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  18. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature. 2015 Jan 29; 517(7536):621-5.
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  19. Xu P, Bailey-Bucktrout S, Xi Y, Xu D, Du D, Zhang Q, Xiang W, Liu J, Melton A, Sheppard D, Chapman HA, Bluestone JA, Derynck R. Innate antiviral host defense attenuates TGF-ß function through IRF3-mediated suppression of Smad signaling. Mol Cell. 2014 Dec 18; 56(6):723-37.
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  20. Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, Niklason L, Calle E, Le A, Randell SH, Rock J, Snitow M, Krummel M, Stripp BR, Vu T, White ES, Whitsett JA, Morrisey EE. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell. 2014 Aug 07; 15(2):123-38.
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