Rosemary Akhurst, PhD

Professor
Director, Pre-Clinical Therapeutics
Helen Diller Family Comprehensive Cancer Center
RAkhurst@cc.ucsf.edu

How do components of the TGF-b signaling pathway regulate mammalian developmental processes and disease outcomes in vivo? This is the overarching question that we address in our lab. We study developmental and tumor angiogenesis, as well as various processes of tumorigenesis. TGF-b is required for normal embryonic development, especially vascular development and immune tolerance, and is a major player in tumor progression, including epithelial mesenchymal transformation and cancer stem cell maintenance. This cytokine is also an important regulator of the tumor microenvironment, driving angiogenesis, immune-suppression, and elaboration of the extracellular matrix, all activities that drive tumor progression and metastasis.

We investigate how genetic variation between individuals regulates the phenotypic output of TGFb signaling, at both the cellular and molecular levels. For example, during embryogenesis and in adult disease models, we have shown that variable outcomes of genetic or pharmacological downregulation of TGFb signaling are determined by variation at genetic modifier loci/genes1-3. Elucidating the molecular mechanisms by which genetic variation in these modifier loci alter TGFb-dependent phenotypes will provide a deeper understanding of in vivo signaling mechanisms, may lead to development of better drugs, and/or provide personalized approaches to TGFb blocking therapeutics. 

In Cancer:  

TGF-b signaling blockade has attracted much attention as a therapeutic approach to cancer4,5. We primarily utilize the multistage chemically-induced carcinogenesis model of cutaneous squamous cell carcinoma (cSCC), which is an excellent model for SCC of the head and neck, lung, bladder and esophagus. We find that blockade of TGF-b signaling can dramatically enhance the efficacy of checkpoint blockade immunotherapy in this model (unpublished). Using genomics and tumor immunology approaches, we are currently investigating molecular mechanisms driving this anti-tumor interaction, as well as tumor autonomous and microenvironmental factors that cause intrinsic drug resistance and mechanisms of acquired resistance to drug treatment. We are also asking how genetic variants at Tgfbm modifier loci 2 influence TGFb-driven primary tumor growth and metastasis, and whether these same modifiers can predict responses to aTGF-b and/or aPD-1 therapy (and how).

In Vascular Development:

We study rare human genetic diseases, caused by loss of function mutations in TGFb-BMP signaling components to investigate the impact of TGFb signaling on development and disease. Hereditary Hemorrhagic Telangiectasia (HHT), which is caused by loss of single allele of either ENG, encoding endoglin, or ACVRL1 encoding Alk1, is a bleeding disorder due to defects in vascular integrity and remodeling1,2,6. We are currently investigating circulating endothelial progenitor cells and immune cells from HHT patients to provide deeper molecular insight into altered cellular properties and signaling pathways in human HHT, and to develop predictive markers of disease severity, which is also influenced by genetic modifiers1. We also undertake studies in mouse models of HHT and in vitro.  

1.         Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, et al. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun. 2012;3:616.

2.         Kawasaki K, Freimuth J, Meyer DS, Lee MM, Tochimoto-Okamoto A, Benzinou M, et al. Genetic variants of Adam17 differentially regulate TGFbeta signaling to modify vascular pathology in mice and humans. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(21):7723-8. PMCID: 4040598.

3.         Freimuth J, Clermont FF, Huang X, DeSapio A, Tokuyasu TA, Sheppard D, et al. Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(44):18042-7. PMCID: 3497801.

4.         Akhurst RJ, Hata A. Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012;11(10):790-811.

5.         Akhurst RJ. Targeting TGF-beta signaling for therapeutic gain. In: Miyazono K, Derynck R, editors. Transforming growth factor beta. Woodbury, New York CSH Perspectives, Cold Spring Harbor Laboratory Press; 2016.

6.         Letteboer TG, Benzinou M, Merrick CB, Quigley DA, Zhau K, Kim IJ, et al. 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. Frontiers in Genetics. 2015;6:67. PMCID: 4357294.

Research Summary: 
Growth factors and genetic modifiers in vascular biology and cancer

Websites

Publications: 

ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-ß-Induced Smad Activation.

PLoS biology

Muthusamy BP, Budi EH, Katsuno Y, Lee MK, Smith SM, Mirza AM, Akhurst RJ, Derynck R

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.

Frontiers in genetics

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

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking aVß8-TGFß signaling in the brain.

Development (Cambridge, England)

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

Genetic variants of Adam17 differentially regulate TGFß signaling to modify vascular pathology in mice and humans.

Proceedings of the National Academy of Sciences of the United States of America

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

BMP-9 balances endothelial cell fate.

Proceedings of the National Academy of Sciences of the United States of America

Derynck R, Akhurst RJ

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.

The Journal of investigative dermatology

Kang HC, Quigley DA, Kim IJ, Wakabayashi Y, Ferguson-Smith MA, D'Alessandro M, Birgitte Lane E, Akhurst RJ, Goudie DR, Balmain A

Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

Proceedings of the National Academy of Sciences of the United States of America

Freimuth J, Clermont FF, Huang X, DeSapio A, Tokuyasu TA, Sheppard D, Akhurst RJ

Targeting the TGFß signalling pathway in disease.

Nature reviews. Drug discovery

Akhurst RJ, Hata A

The paradoxical TGF-ß vasculopathies.

Nature genetics

Akhurst RJ

Complexities of TGF-ß targeted cancer therapy.

International journal of biological sciences

Connolly EC, Freimuth J, Akhurst RJ

TGF-ß-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion.

Journal of cell science

Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R

Defective retinal vascular endothelial cell development as a consequence of impaired integrin aVß8-mediated activation of transforming growth factor-ß.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Arnold TD, Ferrero GM, Qiu H, Phan IT, Akhurst RJ, Huang EJ, Reichardt LF

Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.

Nature communications

Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, Akhurst RJ

The complexities of TGF-ß action during mammary and squamous cell carcinogenesis.

Current pharmaceutical biotechnology

Connolly EC, Akhurst RJ

TGFß1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo.

Clinical cancer research : an official journal of the American Association for Cancer Research

Bouquet F, Pal A, Pilones KA, Demaria S, Hann B, Akhurst RJ, Babb JS, Lonning SM, DeWyngaert JK, Formenti SC, Barcellos-Hoff MH

Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TßRI/II kinase inhibition with LY2109761.

Cancer research

Connolly EC, Saunier EF, Quigley D, Luu MT, De Sapio A, Hann B, Yingling JM, Akhurst RJ

Taking thalidomide out of rehab.

Nature medicine

Akhurst RJ

Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

Clinical cancer research : an official journal of the American Association for Cancer Research

Harradine KA, Ridd K, Saunier EF, Clermont FF, Perez-Losada J, Moore DH, Epstein EH, Bastian BC, Akhurst RJ

Transforming growth factor-beta in breast cancer: too much, too late.

Breast cancer research : BCR

Barcellos-Hoff MH, Akhurst RJ

The type I TGF-beta receptor is covalently modified and regulated by sumoylation.

Nature cell biology

Kang JS, Saunier EF, Akhurst RJ, Derynck R

TGF beta inhibition for cancer therapy.

Current cancer drug targets

Saunier EF, Akhurst RJ

Large- and small-molecule inhibitors of transforming growth factor-beta signaling.

Current opinion in investigational drugs (London, England : 2000)

Akhurst RJ

Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility.

Proceedings of the National Academy of Sciences of the United States of America

Mao JH, Saunier EF, de Koning JP, McKinnon MM, Higgins MN, Nicklas K, Yang HT, Balmain A, Akhurst RJ

Mutations of TGFbeta signaling molecules in human disease.

Annals of medicine

Harradine KA, Akhurst RJ

Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis.

Genomics

Tang Y, Lee KS, Yang H, Logan DW, Wang S, McKinnon ML, Holt LJ, Condie A, Luu MT, Akhurst RJ

TGF beta signaling in health and disease.

Nature genetics

Akhurst RJ

Cancer: dangerous liaisons.

Nature

Balmain A, Akhurst RJ

Mouse strain-dependent heterogeneity of resting limbal vasculature.

Investigative ophthalmology & visual science

Chan CK, Pham LN, Chinn C, Spee C, Ryan SJ, Akhurst RJ, Hinton DR

Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(-/-) mice.

Human molecular genetics

Tang Y, McKinnon ML, Leong LM, Rusholme SA, Wang S, Akhurst RJ

Transforming growth factor-beta1 mediates cellular response to DNA damage in situ.

Cancer research

Ewan KB, Henshall-Powell RL, Ravani SA, Pajares MJ, Arteaga C, Warters R, Akhurst RJ, Barcellos-Hoff MH

Metastasis is driven by sequential elevation of H-ras and Smad2 levels.

Nature cell biology

Oft M, Akhurst RJ, Balmain A

TGF-beta antagonists: why suppress a tumor suppressor?

The Journal of clinical investigation

Akhurst RJ

Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation.

The American journal of pathology

Ewan KB, Shyamala G, Ravani SA, Tang Y, Akhurst R, Wakefield L, Barcellos-Hoff MH

TGF-beta signaling in cancer--a double-edged sword.

Trends in cell biology

Akhurst RJ, Derynck R

TGF-beta signaling in tumor suppression and cancer progression.

Nature genetics

Derynck R, Akhurst RJ, Balmain A

Epithelial carcinogenesis in the mouse: correlating the genetics and the biology.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Frame S, Crombie R, Liddell J, Stuart D, Linardopoulos S, Nagase H, Portella G, Brown K, Street A, Akhurst R, Balmain A

Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion.

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

Portella G, Cumming SA, Liddell J, Cui W, Ireland H, Akhurst RJ, Balmain A

Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice.

Nature genetics

Bonyadi M, Rusholme SA, Cousins FM, Su HC, Biron CA, Farrall M, Akhurst RJ

Altered epidermal cell growth control in vivo by inducible expression of transforming growth factor beta 1 in the skin of transgenic mice.

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

Fowlis DJ, Cui W, Johnson SA, Balmain A, Akhurst RJ

The TGF beta type II receptor, Tgfbr2, maps to distal mouse chromosome 9.

Genomics

Bonyadi M, Cui W, Nagase H, Akhurst RJ

Liposome-medicated gene transfer and expression via the skin.

Human molecular genetics

Alexander MY, Akhurst RJ

Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice.

Development (Cambridge, England)

Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ

Circulating human factor IX produced in keratin-promoter transgenic mice: a feasibility study for gene therapy of haemophilia B.

Human molecular genetics

Alexander MY, Bidichandani SI, Cousins FM, Robinson CJ, Duffie E, Akhurst RJ

Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice.

Genes & development

Cui W, Fowlis DJ, Cousins FM, Duffie E, Bryson S, Balmain A, Akhurst RJ

Analysis of homozygous TGF beta 1 null mouse embryos demonstrates defects in yolk sac vasculogenesis and hematopoiesis.

Annals of the New York Academy of Sciences

Martin JS, Dickson MC, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ

Localization of transforming growth factor-alpha RNA and protein in the skin of psoriatic patients receiving therapy.

The British journal of dermatology

Watts P, Stables GS, Akhurst RJ, Mackie RM

RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development.

Development (Cambridge, England)

Dickson MC, Slager HG, Duffie E, Mummery CL, Akhurst RJ

Positive and negative growth control in multistage skin carcinogenesis.

Recent results in cancer research. Fortschritte der Krebsforschung. Progre`s dans les recherches sur le cancer

Brown K, Kemp CJ, Burns PA, Stoler AB, Fowlis DJ, Akhurst RJ, Balmain A

Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo.

Developmental genetics

Martin P, Dickson MC, Millan FA, Akhurst RJ

The role of TGF-beta s in mammalian development and neoplasia.

Molecular reproduction and development

Akhurst RJ, Fitzpatrick DR, Fowlis DJ, Gatherer D, Millan FA, Slager H

Discordant transforming growth factor beta 1 RNA and protein localization during chemical carcinogenesis of the skin.

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

Fowlis DJ, Flanders KC, Duffie E, Balmain A, Akhurst RJ

Functional loss of tumour suppressor genes in multistage chemical carcinogenesis.

Princess Takamatsu symposia

Balmain A, Kemp CJ, Burns PA, Stoler AB, Fowlis DJ, Akhurst RJ

Expression of TGF-beta isoforms during first trimester human embryogenesis.

Development (Cambridge, England)

Gatherer D, Ten Dijke P, Baird DT, Akhurst RJ

Localization of elevated transforming growth factor-alpha in psoriatic epidermis.

The Journal of investigative dermatology

Turbitt ML, Akhurst RJ, White SI, MacKie RM

Differential expression of TGF beta isoforms in murine palatogenesis.

Development (Cambridge, England)

Fitzpatrick DR, Denhez F, Kondaiah P, Akhurst RJ

TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis.

Development (Cambridge, England)

Akhurst RJ, Lehnert SA, Faissner A, Duffie E

The role of TGF beta in mouse development.

Annals of the New York Academy of Sciences

Akhurst RJ, Lehnert SA, Gatherer D, Duffie E

Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis.

Environmental health perspectives

Bailleul B, Brown K, Ramsden M, Akhurst RJ, Fee F, Balmain A

The action of oncogenes and growth factors in tumour initiation and promotion.

Carcinogenesis; a comprehensive survey

Akhurst R, Bailleul B, Brown K, Ramsden M, Fee F, Balmain A

Molecular analysis of chemical carcinogenesis in the skin.

The British journal of cancer. Supplement

Balmain A, Brown K, Akhurst RJ, Fee FM

Sea urchin actin gene linkages determined by genetic segregation.

Developmental biology

Minor JE, Lee JJ, Akhurst RJ, Leahy PS, Britten RJ, Davidson EH

Structure and organization of the CyIII actin gene subfamily of the sea urchin, Strongylocentrotus purpuratus.

Journal of molecular biology

Akhurst RJ, Calzone FJ, Lee JJ, Britten RJ, Davidson EH

Sea urchin actin gene subtypes. Gene number, linkage and evolution.

Journal of molecular biology

Lee JJ, Shott RJ, Rose SJ, Thomas TL, Britten RJ, Davidson EH

Dev. Biol

Differential expression of the actin gene family of Strongylocentrotus purpuratus

Akhurst RJ, Shott RJ, Lee JJ, Britten RJ, Davidson EH

Regulation of the relative abundances of mRNAs in hepatoma and liver.

Advances in experimental medicine and biology

Birnie GD, Jacobs H, Shott R, Wilkes PR

Post-transcriptional control of messenger abundance.

Molecular biology reports

Birnie GD, Balmain A, Jacobs H, Shott R, Wilkes PR, Paul J