Research Summary

I am a UCSF Professor of Anatomy in the Helen Diller Family Comprehensive Cancer Center in San Francisco. My laboratory has for many years studied the role of TGFβ signaling in cancer, development, and vascular biology. We primarily study chemically-induced carcinomas, namely DMBA/TPA-induced cutaneous squamous cell carcinomas that are heterogenous and share many genetic features with human cancers. Our studies were the first to show that TGFβ1 is induced by tumor promotion and can play both positive and negative roles in tumor initiation and progression in vivo. We have shown that this growth factor is important in cancer stem cell maintenance, and a major regulator of the tumor microenvironment including angiogenesis and potent immune-suppression, all activities that drive tumor metastasis. Currently, we undertake translational studies investigating how targeting of distinct TGFβ signaling components can be used therapeutically, particularly to augment immunotherapy, and our studies have contributed to the initiation of ongoing clinical trials of novel anti-TGFβ signaling agents by Novartis and Pfizer. We also use mouse models to investigate how germline variants influence responses to immunotherapy, particularly through effects on tumor immunity and the tumor microenvironment. Additionally, we have a strong interest in the cellular and molecular mechanisms driving abnormal vascular biology in the human genetic disorder Hereditary Hemorrhagic Telangiectasia, that results from loss of function mutations in genes encoding TGFβ/BMP signaling molecules, endoglin, ACVRL1/Alk1, or Smad4, and the influence of germline genetic variants on HHT disease progression. Our studies often involve large collaborative teams.

As Faculty Director of the NCI-sponsored CCSG Preclinical Therapeutics Core (PTC), my interest is in providing access to state-of-the-art technology and technical support for small animal cancer therapeutics and imaging, for members of the HDFCCC scientific community and beyond. Through competitive federal and non-federal awards, we have acquired instrumentation for all three UCSF cancer campuses. These include Vevo770 and Vevo2100 ultrasound imaging platforms, several IVIS Spectrum multichannel fluorescent/ bioluminescent imagers, an Xstrahl small animal micro-CT-guided irradiator, and a high-resolution high through put micro-CT scanner.

Research Funding

  • August 5, 1999 - May 31, 2023 - Cancer Center Support Grant , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P30CA082103
  • January 1, 2018 - December 31, 2021 - Advancing the translatability of mouse models for cancer immunotherapy , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA210561
  • September 1, 2015 - May 31, 2021 - Circulating cells as tools to study vascular pathobiology of HHT , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL122869
  • August 1, 2019 - July 31, 2020 - PerkinElmer Quantum GX CT-imager , Principal Investigator . Sponsor: NIH, Sponsor Award ID: S10OD025022

Education

Imperial College of Science and Technology, University of London, UK, BSc (Hons), 1st class, 1975-1978, Biochemistry
Beatson Institute for Cancer Research, Glasgow, UK, PhD, 1978-1981, Molecular Biology

Honors & Awards

  • 1975, 1976
    Imperial College Entrance Scholarship
  • 1978
    Ewart Stickings Award for Excellence in Biochemistry (Top Biochemistry Student, Imperial College, London)
  • 1978
    Associate of the Royal College of Science
  • 1982-4
    European Molecular Biology Organization (EMBO) Fellowship Award
  • 1984
    "New Blood" Lectureship, London University, UK
  • 2011-2017
    Charter Member NIH VCMB Study Section
    • 2019-current
    Vice-Chair Global Research and Medical Advisory Board of CureHHT
  • 2020
    UCSF Biomedical Sciences (BMS) Program Mentoring Award

Selected Publications

  1. Griffin L, Ho L, Akhurst RJ, Arron ST, Boggs JME, Conlon P, O'Kelly P, Toland AE, Epstein EH, Balmain A, Bastian BC, Moloney FJ, Murphy GM, Laing ME. Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients. Skin Health Dis. 2022 Jun; 2(2):e95.  View on PubMed
  2. Szu-Ying Chen, Ons Mamäi, Rosemary J. Akhurst. TGFß: Signaling Blockade for Cancer Immunotherapy. Annual Review of Cancer Biology. 2021 Dec 22; 6(1):1-24.  View on PubMed
  3. Dodagatta-Marri E, Ma HY, Liang B, Li J, Meyer DS, Chen SY, Sun KH, Ren X, Zivak B, Rosenblum MD, Headley MB, Pinzas L, Reed NI, Del Cid JS, Hann BC, Yang S, Giddabasappa A, Noorbehesht K, Yang B, Dal Porto J, Tsukui T, Niessen K, Atakilit A, Akhurst RJ, Sheppard D. Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Rep. 2021 07 06; 36(1):109309.  View on PubMed
  4. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021 01; 18(1):9-34.  View on PubMed
  5. Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD, Binnewies M, Broz ML, Mori H, Wu D, Adoumie M, Del Rosario R, Li O, Buchmann T, Liang B, Malato J, Arce Vargus F, Sheppard D, Hann BC, Mirza A, Quezada SA, Rosenblum MD, Krummel MF, Balmain A, Akhurst RJ. α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer. 2019 03 04; 7(1):62.  View on PubMed
  6. Katsuno Y, Meyer DS, Zhang Z, Shokat KM, Akhurst RJ, Miyazono K, Derynck R. Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition. Sci Signal. 2019 02 26; 12(570).  View on PubMed
  7. Budi EH, Mamai O, Hoffman S, Akhurst RJ, Derynck R. Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells. iScience. 2019 Jan 25; 11:474-491.  View on PubMed
  8. Mamai O, Dodagatta-Marri E, Akhurst RJ. From prevention to cure, repurposing anti-viral vaccines for cancer immunotherapy. Biotarget. 2018 Dec; 2.  View on PubMed
  9. Du D, Katsuno Y, Meyer D, Budi EH, Chen SH, Koeppen H, Wang H, Akhurst RJ, Derynck R. Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition. EMBO Rep. 2018 01; 19(1):135-155.  View on PubMed
  10. Akhurst RJ. Targeting TGF-β Signaling for Therapeutic Gain. Cold Spring Harb Perspect Biol. 2017 Oct 03; 9(10).  View on PubMed
  11. Muthusamy BP, Budi EH, Katsuno Y, Lee MK, Smith SM, Mirza AM, Akhurst RJ, Derynck R. ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-β-Induced Smad Activation. PLoS Biol. 2015 Dec; 13(12):e1002325.  View on PubMed
  12. Megan Murnane, Eugen Dhimolea, Ruojing Li, Megan A. Bariteau, Diamond D. Wheeler, Rosemary J. Akhurst, Aaron C. Logan, Pamela Munster, Arun Wiita, Thomas G. Martin, Jeffrey L. Wolf, Jun O. Liu, Constantine S. Mitsiades, Blake T. Aftab. Defining Primary Marrow Microenvironment-Induced Synthetic Lethality and Resistance for 2,684 Approved Drugs Across Molecularly Distinct Forms of Multiple Myeloma. Blood. 2015 Dec 3; 126(23):503-503.  View on PubMed
  13. Akhurst RJ, Padgett RW. Matters of context guide future research in TGFβ superfamily signaling. Sci Signal. 2015 Oct 20; 8(399):re10.  View on PubMed
  14. Letteboer TG, Benzinou M, Merrick CB, Quigley DA, Zhau K, Kim IJ, To MD, Jablons DM, van Amstel JK, Westermann CJ, Giraud S, Dupuis-Girod S, Lesca G, Berg JH, Balmain A, Akhurst RJ. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet. 2015; 6:67.  View on PubMed
  15. Arnold TD, Niaudet C, Pang MF, Siegenthaler J, Gaengel K, Jung B, Ferrero GM, Mukouyama YS, Fuxe J, Akhurst R, Betsholtz C, Sheppard D, Reichardt LF. Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain. Development. 2014 Dec; 141(23):4489-99.  View on PubMed
  16. Kawasaki K, Freimuth J, Meyer DS, Lee MM, Tochimoto-Okamoto A, Benzinou M, Clermont FF, Wu G, Roy R, Letteboer TG, Ploos van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Westermann CJ, Coffey RJ, Akhurst RJ. Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci U S A. 2014 May 27; 111(21):7723-8.  View on PubMed
  17. Derynck R, Akhurst RJ. BMP-9 balances endothelial cell fate. Proc Natl Acad Sci U S A. 2013 Nov 19; 110(47):18746-7.  View on PubMed
  18. Kang HC, Quigley DA, Kim IJ, Wakabayashi Y, Ferguson-Smith MA, D'Alessandro M, Birgitte Lane E, Akhurst RJ, Goudie DR, Balmain A. Multiple self-healing squamous epithelioma (MSSE): rare variants in an adjacent region of chromosome 9q22.3 to known TGFBR1 mutations suggest a digenic or multilocus etiology. J Invest Dermatol. 2013 Jul; 133(7):1907-10.  View on PubMed
  19. Rosemary J. Akhurst, Akiko Hata. Erratum: Targeting the TGFß signalling pathway in disease. Nature Reviews Drug Discovery. 2012 Nov 1; 11(11):886-886.  View on PubMed
  20. Freimuth J, Clermont FF, Huang X, DeSapio A, Tokuyasu TA, Sheppard D, Akhurst RJ. Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc Natl Acad Sci U S A. 2012 Oct 30; 109(44):18042-7.  View on PubMed

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