Rosemary Akhurst, PhD

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/genes^1-3. 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 cancer^4,5. 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blockade of TGF-b signaling can dramatically enhance the efficacy of checkpoint blockade immunotherapy in this model (unpublished).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 remodeling^1,2,6. 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.