Research Summary

As a UCSF Professor of Anatomy in the Helen Diller Family Comprehensive Cancer Center, my laboratory studies the roles and mechanism of action of TGFβ signaling in cancer, development, and vascular biology. We investigate chemically-induced carcinomas, namely DMBA/TPA-induced cutaneous squamous cell carcinomas that are genetically heterogenous and share many features with human cancers. Our studies were the first to show that TGFβ1 is induced by tumor promotion and that it can play both positive and negative roles in tumor initiation and progression in vivo. TGF has pleiotropic activity and we showed that this growth factor can drive epithelial-mesenchymal transformation of tumor cells and cancer stem cell maintenance. It is also a major regulator of the tumor microenvironment through its effects on vascular cells, angiogenesis, and as a potent immune-suppressor, all activities that drive tumor progression and metastasis.

Currently, we undertake translational studies investigating how targeting of distinct TGFβ signaling components can be used therapeutically, particularly to augment cancer immunotherapy, and our studies have contributed to the initiation of ongoing oncology clinical trials of novel anti-TGFβ signaling agents by Novartis and Pfizer. We are interested in the influence of genetic background on responses to cancer therapies. As such. we use mouse models to investigate how germline genetic variants influence responses to immunotherapies through effects on tumor immunity and the tumor microenvironment. 
Finally, we have a deep interest in the cellular and molecular mechanisms involved in maintenance of vascular integrity, and how these go awry in disease states, such as in the vascular pathology of the human genetic disorder, Hereditary Hemorrhagic Telangiectasia (HHT). HHT results from germline loss of function mutations in genes encoding TGFβ/BMP signaling molecules, endoglin, ACVRL1/Alk1, or Smad4, and HHT disease progression is influenced by germline genetic variants and by environmental factors such as inflammation and wounding. 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 Perkin Elmer IVIS Spectrum multichannel fluorescent/ bioluminescent imagers, an Xstrahl small animal micro-CT-guided irradiator, and a Perkin Elmer, high-resolution high through put micro-CT scanner.
 

Research Funding

  • March 17, 2023 - February 28, 2027 - Protein tyrosine phosphatase non-receptor 14 in vascular stability and remodeling , Principal Investigator . Sponsor: NIH/NHLBI, Sponsor Award ID: 1R01HL164891
  • September 1, 2018 - August 31, 2023 - University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center (UCaMP) to Reduce Cancer Health Disparities , CO-INVESTIGATOR (UCSF SITE PI) . Sponsor: NIH/NCI, Sponsor Award ID: U54233306
  • 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

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. Szu-Ying Chen, Ons Mamai, Rosemary Akhurst. Abstract 3420: Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment. Cancer Research. 2022 Jun 15; 82(12_Supplement):3420-3420.  View on PubMed
  2. 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
  3. Chen SY, Mamai O, Akhurst RJ. TGFβ: Signaling Blockade for Cancer Immunotherapy. Annu Rev Cancer Biol. 2022; 6(1):123-146.  View on PubMed
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Akhurst RJ. Targeting TGF-β Signaling for Therapeutic Gain. Cold Spring Harb Perspect Biol. 2017 Oct 03; 9(10).  View on PubMed
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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

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