Professor Andrew Tee

(he/him)

BSc (Hons), PhD

Publication

• Date
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Research

Tuberous Sclerosis Complex

I became interested in TSC at Harvard, where I was involved in a number of key studies on the upstream control of mTOR by insulin/PI 3-kinase and protein kinase B (PKB/Akt), and by the small G-protein Rheb. I identified the TSC gene product, TSC2 as a direct substrate for PKB/Akt as well as a downstream target within the mitogen activated protein kinase (MAPK) pathway. I also discovered that the TSC1/2 heterodimer specifically inhibited signalling through mTOR, and that this was due to the increased GTPase activity towards novel small G-proteins called Rheb and RhebL1. I am considered a leading expert on Rheb, and within the UK, I am the only researcher with an established lab working exclusively on TSC and mTOR at the protein level and who is directly tied in with genetics and clinicians. My follow-up work in the UK revealed that mTOR directly regulated the transcriptional activity of Hypoxic Inducible Factor 1alpha (HIF1alpha), and Signal transducer and activator of transcription 3 (STAT3) and is involved in cancer progression in TSC. Collectively, my research on TSC uncovered that the TSC1 and TSC2 gene products inhibited cell growth through repression of mTOR. This fundamental research was then translated into the clinical setting for the treatment of TSC patients with the use of the mTOR inhibitor, rapamycin. Consequently, the Division of Cancer and Genetics within Cardiff University completed a phase II clinical trial of the safety and efficacy of sirolimus therapy (a rapamycin analogue) for renal angiomyolipomas in patients with TSC. My strong cellular biology research background on TSC and mTOR signalling fits strategically into the current research on TSC within the division. We work closely as a TSC research team with clinicians and geneticists at Cardiff to find cellular mechanisms that can be exploited for potential therapy.

Birt-Hogg-Dubé

I also became interested in BHD, as the features observed are similar to that seen in TSC patients, but the tumour suppressor function of BHD is unknown. We believe that BHD is necessary for maintaining cell homeostasis, where loss of function of BHD leads to tumour progression. We also believe that BHD is involved in progression of sporadic cancers. Through biochemical and cell biology techniques, we recently uncovered several facets of tumour suppressor function of BHD. We know that BHD is involved in ciliogenesis and in the regulation of cell metabolism through HIF1alpha, AMP-dependent protein kinase (AMPK) and autophagy.

Research statement

By understanding fundamental genetic diseases such as TSC, BHD, and NF1, my research team hopes to uncover new therapeutic strategies that are also transferable for other human diseases.

Contribution to Science

1] My early contribution as a Wellcome Trust Prize PhD Student revealed that signal transduction through mTORC1 was intimately involved in the cell death response upon treatment with DNA-damaging agents. This work uncovered that mTORC1 was potentially down regulated during the pre-commitment stages of apoptosis (as a survival mechanism), and that rapamycin treatment could delay cell death induced upon DNA damage (this work was the first to show that rapamycin enhanced cell survival). I also discovered the RAIP motif within the N-terminus of eukaryotic initiation factor 4E-Binding protein 1 (4E-BP1) which is lost via cleavage in a caspase-3 dependent manner. Cleavage of 4E-BP1 leads to dominant inhibition of cap-dependent translation as the cleaved isoform of 4E-BP1 is no longer a substrate to mTORC1 and constitutively binds to and represses eIF4E. These early studies formed a solid research foundation for my future scientific contributions regarding mechanisms of mTORC1 signal transduction.

2] When I was an EMBO Travelling Post-doctoral Fellow (in Prof John Blenis’s lab at Harvard), I made several major contributions to research regarding TSC. I was a key member involved in a number of collaborative studies on signal dissection of the TSC1/TSC2 tumor suppressor complex (which was unknown at that time). I was involved in researching the upstream control of mTORC1 by protein kinase B (PKB/Akt) and TSC1/TSC2, and by the small G-protein Rheb. I identified that TSC2 was also a downstream target within the mitogen activated protein kinase (MAPK) pathway. Since these pioneering studies, I have been involved in many collaborative studies to better understand TSC1/TSC2 at the protein level, involving regulation of its localisation by PKB/Akt and targeting of a sub-pool of TSC1/TSC2 to the peroxisome (which we believe regulates metabolic homeostasis).

3] As a Intermediate BHF and Career Development AICR Research Fellow, I discovered several new cell signalling mechanisms relating to TSC, involved in cell survival and gene-expression control. I revealed that mTORC1 directly regulates the transcriptional activity of Hypoxic Inducible Factor 1α (HIF1α), which is critically involved in angiogenesis and tumour progression linked to TSC pathology. We later uncovered that mTORC1 was upstream of STAT3, and STAT3 is necessary for gene expression of HIF1α. This is an important contribution that uncovers a new signaling mechanism that is directly linked to angiogenic signaling. Sequentially, I also demonstrated that aberrant signalling through JAK2/STAT3 and HIF-1α drives tumour progression within multiple malignant peripheral nerve sheath tumours (MPNSTs) from Neurofibromatosis type 1 patients, indicating that inhibition of the STAT3/HIF-1α/VEGF-A signalling axis could be a viable therapeutic strategy to treat MPNSTs. By screening a panel of clinically approved drugs, I also discovered that nelfinavir and chloroquine selectively kills TSC2-deficient cell lines, indicating that targeting endoplasmic reticulum stress in combination with lysosomal inhibition could be a viable strategy to treat TS patients.

4] I have also contributed to our basic understanding of mTORC1. A key discovery was identifying that autophagy potently represses mTORC1 activity through ULK1-mediated phosphorylation of Raptor, which prevents mTORC1 substrate binding to Raptor. I was the first to definitely show that Raptor recruits substrates to mTORC1 for efficient phospho-transfer, and designed the Raptor far-western assay to characterise mTORC1 substrate docking to Raptor.

5] I have made significant contributions to the understanding of a related genetic disorder to TSC, called Birt-Hogg-Dubé (BHD), where we have identified several new mechanisms of tumour suppression of Folliculin (FLCN). I have shown that FLCN represses HIF-1α, where loss of FLCN causes metabolic transformation regarding heightened mitochondrial activity, reactive oxygen species and AMPK activation. I have shown that FLCN also functions as a driver of basal autophagy, at the level of autophagosomal flux and is a new substrate of ULK1. I was also involved in the collaborative study that revealed that BHD syndrome is a novel ciliopathy, where FLCN is involved in ciliogenesis.

Biography

Education and Qualifications:

1998          B.Sc. Hons Biochemistry (i) first-class    Dundee University (Dundee, United Kingdom)

2001          Ph.D. Biochemistry                                 Dundee University (Dundee, United Kingdom)

Career Overview:

2019 - present     Professor, Principal Investigator, Division of Cancer and Genetics, Cardiff University, UK.

2017 - 2019         Reader, Principal Investigator, Division of Cancer and Genetics, Cardiff University, UK.

2012 - 2017         Senior Lecturer, Principle Investigator, Division of Cancer and Genetics, Cardiff University

2007 - 2012         Non-Clinical Research Lecturer, Principle Investigator, Institute of Medical Genetics, Cardiff University

2004 - 2007         Independent investigator, Laboratory of Prof. Grahame D. Hardie, University of Dundee,

2001 - 2004         Postdoctoral Fellow, Laboratory of Prof. John Blenis, Harvard Medical School, Boston, MA.

1998 - 2001         Ph.D. student, Laboratory of Prof. Christopher G. Proud, University of Dundee

Honours and awards

2007 - 2013         Association for International Cancer Research Career Development Fellowship

2004 - 2007         British Heart Foundation Intermediate Research Fellowship

2003 - 2004         European Molecular Biology Organization Postdoctoral Fellowship

1998 - 2001         Wellcome Trust Prize Studentship

1998                     1st class Honors in Biochemistry, University of Dundee

Professional memberships

2021 - present     Myrovlytis Trust Scientific Advisor

2011 - present     Lymphangioleiomyomatosis (LAM) Foundation Scientific Advisor

2007 - present     Tuberous Sclerosis Association Scientific Advisor

2003 - present     Tuberous Sclerosis Alliance Grant Review Committee and Scientific Advisor

2003 - present     Hospital Saturday Fund Scientific Advisor and Association Member

2012 - present     Editorial Board Member for Cancers

2012 - present     Guest editor for Biochemical Journal

2013 - present     Guest editor for Seminars in Cell and Developmental Biology

2013 - 2016         FindACure Scientific Advisor