Dr David Bryant - Epithelial Polarity
Introduction
Our lab focuses on a fundamental, yet largely unanswered question: How is the normal organisation of tissue disrupted to allow cells to form disarrayed tumours?
Cells of many tissues are polarised - that is that cells collectively form configurations tailored to the needs of a tissue. During tumourigenesis, this exquisite organisation is lost. Despite loss of tissue polarity being an obligate event in cancer progression, we know little about this basic process.
We use mini-avatars of tumours ex vivo to understand how cells collectively organise. Our efforts are focused on prostate, colorectal and ovarian cancers. We take two approaches to unravel the complexity of this process:
1) Building new tools to analyse tumour avatars ex vivo
2) Identifying the signalling processes that drive collective tumour invasion and metastasis.
We collaborate extensively for a multi-disciplinary approach to understand tumour metastasis (Sansom, Zanivan, Blyth, Leung, Miller Labs).
To develop better tools to understand how tumour cells loose polarity, we have developed cutting-edge, high-content microscopy and computational image analysis of tumour spheroids and organoids. Molecularly, we focus on two pathways: the ARF GTPases (and their regulators and effectors, which we call the 'ARF regulome'), and the role of the cell surface protein, Podocalyxin. Both molecules are highly overexpressed in metastatic prostate cancer tumours.
Our ultimate aim is to investigate such changes in cell polarity as potential future biomarkers of cancer in patients, and possible targets for future therapeutic interventions.
EmailCell scientist to watch − David Bryant
Click here to read David's interview with the Journal of Cell Science.
Other funding:
Lab Report
Research Highlights
- Elucidation of an ARF GEF-GTPase pathway amplified in cancer patients that controls key lipid (phosphatidylinositol-phosphate) signalling to drive metastasis (BioRxiv, 2019)
- Identification of the key lipid (phosphatidylinositol-phosphate) metabolic pathways that control the formation of an apical surface. This defined that PI(3,4)P2 is a determinant of apical identity (Nat Comms 2018)
- Extensive molecular characterisation of how cells know to orient their apical surfaces in the correct direction. Importantly, this work uncovers one way by which the extracellular matrix determines whether groups of epithelial cells become invasive or form a lumen (Dev Cell 2014)
- First molecular description of the membrane trafficking and polarity rearrangements required to form an apical surface and lumen de novo. Our findings have been recapitulated in many other systems, showing that we uncovered a fundamentally conserved biological process (Nat Cell Biol 2012)
- Discovery of an unexpected role of the EGF receptor in controlling basolateral to apical transport of vesicles. Key to this work was a novel cascade of kinases leading to the vesicle transport protein Rab11FIP5 (Nat Cell Biol 2012)
Key Recent Publications
Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, Bryant DM. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nat Commun. 2021;12:1623.
Hewit K, Sandilands E, Martinez RS, James D, Leung HY, Bryant DM, Shanks E, Markert EK. A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor. Cell Death Dis. 2018; 9: 1069.
Roman-Fernandez A, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, Bryant DM. The phospholipid PI(3,4)P2 is an apical identity determinant. Nat Commun. 2018; 9: 5041.
Biography
Education and qualifications
2006: PhD, University of Queensland, Australia, Supervisor Jennifer Stow
2002: BSc (Hons) Class I, University of Queensland, Australia
Appointments
2014-present: Beatson Associate, CRUK Beatson Institute
2014-present: Senior Lecturer, School of Cancer Sciences, University of Glasgow
2012-2014: Associate Academic Researcher, University of California, San Francisco, USA
2006-2012: Postdoctoral Fellow with Keith Mostov, UC San Francisco, USA
Professional committee membership
2019-present: Editorial Advisory Board, Journal of Cell Science
2019-present: Deputy Chair, Athena Swan Committee, School of Cancer Sciences
2017-present: Affiliate Member, BioRxiv Biology Preprint Server
2015-present: Editorial Board Member, International Review of Cell and Molecular Biology
Honours and awards
2018 Profiled as 'Cell Scientist to watch', Journal of Cell Science
2011 Finalist, U. Queensland 'Young Alumnus of the Year' Award
2007 Postdoctoral Fellowship, Susan G. Komen Breast Cancer Foundation
2005 Cure Cancer Foundation 'Australian Young Researcher of the Year'
Recent Publications
2023
Román-Fernández A, Mansour MA, Kugeratski FG, Anand J, Sandilands E, Galbraith L, Rakovic K, Freckmann EC, Cumming EM, Park J, Nikolatou K, Lilla S, Shaw R, Strachan D, Mason S, Patel R, McGarry L, Katoch A, Campbell KJ, Nixon C, Miller CJ, Leung HY, Le Quesne J, Norman JC, Zanivan S, Blyth K, Bryant DM. Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Sci Adv. 2023;9:eabq1858.
Sandilands E, Freckmann EC, Cumming EM, Román-Fernández A, McGarry L, Anand J, Galbraith L, Mason S, Patel R, Nixon C, Cartwright J, Leung HY, Blyth K, Bryant DM. The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels. Journal of Cell Biology. 2023;222.
2022
Freckmann EC, Sandilands E, Cumming E, Neilson M, Román-Fernández A, Nikolatou K, Nacke M, Lannagan TRM, Hedley A, Strachan D, Salji M, Morton JP, McGarry L, Leung HY, Sansom OJ, Miller CJ, Bryant DM. Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging. Nat Commun. 2022;13:5317.
Kai F, Ou G, Tourdot RW, Stashko C, Gaietta G, Swift MF, Volkmann N, Long AF, Han Y, Huang HH, Northey JJ, Leidal AM, Viasnoff V, Bryant DM, Guo W, Wiita AP, Guo M, Dumont S, Hanein D, Radhakrishnan R, Weaver VM. ECM dimensionality tunes actin tension to modulate endoplasmic reticulum function and spheroid phenotypes of mammary epithelial cells. Embo j. 2022; 41:e109205
Nikolatou K, Sandilands E, Roman-Fernandez A, Cumming EM, Freckmann EC, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant D. PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer. bioRxiv. 2022;Volume:2022.2011.2029.518198.
Román-Fernández Á, Sandilands E, Bryant DM. The Use of Three-Dimensional Cell Culture to Study Apicobasal Polarization and Lumen Formation. Methods Mol Biol. 2022;2438:439-454.
Bristow RG, Engel J, Jayasinghe I, Kampmann M, James Sansom O, Bryant DM. Conversations with LGBT+ scientists about visibility, leadership and climbing the career ladder. Journal of Cell Science. 2022;135.
2021
Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, Bryant DM. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nat Commun. 2021;12:1623.
Nászai M, Bellec K, Yu Y, Román-Fernández A, Sandilands E, Johansson J, Campbell AD, Norman JC, Sansom OJ, Bryant DM, Cordero JB. RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis. Elife. 2021;10:e63807
2020
Millar R, Kilbey A, Remak SJ, Severson TM, Dhayade S, Sandilands E, Foster K, Bryant DM, Blyth K, Coffelt SB. The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer. Molecular oncology. 2020;14: 1868-1880
2019
Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, Juin A, Ismail S, Bryant DM, Markert EK, Machesky LM, Mazzone M, Sansom OJ, Zanivan S. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science signaling 2019; 12: eaan8247
2018
Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, Lilla S, Neilson MP, Tafelmeyer P, Zanivan S, Ismail S, Bryant DM, Tomkinson NCO, Chamberlain LH, Mastick GS, Insall RH, Machesky LM. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol. 2018; 20: 1159-71
Hewit K, Sandilands E, Martinez RS, James D, Leung HY, Bryant DM, Shanks E, Markert EK. A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor. Cell Death Dis. 2018; 9: 1069.
Roman-Fernandez A, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, Bryant DM. The phospholipid PI(3,4)P2 is an apical identity determinant. Nat Commun. 2018; 9: 5041.
Stehbens SJ, Ju RJ, Adams MN, Perry S, Haass NK, Bryant DM, Pollock PM. FGFR2b activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer. J Cell Sci 2018; 131:
2017
Datta A, Sandilands E, Mostov KE, Bryant DM. Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cell Signal 2017; 40: 91-8
Gao L, Yang Z, Hiremath C, Zimmerman SE, Long B, Brakeman PR, Mostov KE, Bryant DM, Luby-Phelps K, Marciano DK. Afadin orients cell division to position the tubule lumen in developing renal tubules. Development 2017; 144: 3511-20
Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J 2017; 36: 2373-89
Ruch TR, Bryant DM, Mostov KE, Engel JN. Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity. Mol Biol Cell 2017; 28: 252-60
Bryant D, Johnson A. Meeting report - Intercellular interactions in context: towards a mechanistic understanding of cells in organs. J Cell Sci 2017; 130: 2083-85
2016
Yang Z, Zimmerman SE, Tsunezumi J, Braitsch C, Trent C, Bryant DM, Cleaver O, Gonzalez-Manchon C, Marciano DK. Role of CD34 family members in lumen formation in the developing kidney. Dev Biol. 2016; 418: 66-74
Bryant DM, Yap AS. Editorial overview: Membrane traffic and cell polarity. Traffic. 2016; 17: 1231-2
Roman-Fernandez A, Bryant DM. Complex polarity: Building multicellular tissues through apical membrane traffic. Traffic. 2016; 17: 1244-61,
Lab Members
Postdoctoral Scientist
Archana Katoch (University of Glasgow)
Scientific Officer
Emma Sandilands (University of Glasgow)
PhD Students
Amy Bryson (UKRI)
Erin Cumming (University of Glasgow Doctoral Training Program)
Former Lab Members
Mohammed Mansour (Royal Society Newton International Fellowship)
Narissa Parry, PhD rotation Student (Paul O'Gorman Leukaemia Research Centre)
Dr Marisa Nacke, PhD Student (Boston Consulting Group, Germany)
