Charles Streuli is elucidating the involvement of extracellular matrix and integrin signalling in normal mammary gland biology and early breast cancer.

Professor of Cell Biology

Wellcome Trust Centre for Cell-Matrix Research
The University of Manchester
Michael Smith Building
Oxford Road
Manchester
M13 9PT

Tel: +44 (0)161 275 5626
Email: cstreuli@manchester.ac.uk

Charles obtained his first degree in Biochemistry at the University of Cambridge. He studied for a PhD at the University of Leicester with David Critchley, the CRUK executive director of science. This was followed by postdoctoral work on the 5th floor of the Imperial Cancer Research Fund Laboratories in London, with Beverly Griffin. Charles then carried out a long-term EMBO-fellowship and a Fogarty International fellowship at the Lawrence Berkeley National Laboratory in California, with Mina Bissell, the president of the American Society of Cell Biology. He was then awarded a Senior Research Fellowship in Basic Biomedical Science by the Wellcome Trust to set up his own laboratory at the University of Manchester in 1992.

Charles jointly established the Manchester Breast Centre, a pan-Manchester organisation uniting basic and clinical scientists working on mammary gland biology and breast cancer in 2005, and co-founded the Manchester Breakthrough Breast Cancer Research Unit in 2009. He was appointed to the position of Director of the Wellcome Trust Centre for Cell-Matrix Research from 2009 to 2014. Charles has also served on the board of the British Society of Cell Biology, on research committees for the Medical Research Council and Cancer Research UK, and was elected to become a Fellow of the Royal Society of Biology in 2013.

Research

Charles’ scientific achievements have been to discover mechanisms by which cell-matrix interactions control developmental morphogenesis, survival and proliferation, as well as tissue-specific gene expression, in epithelial tissues. By focusing on breast biology, he revealed the central role of integrin adhesion receptors in mammalian cell behaviour, providing a general framework for understanding epithelial tissue development and function.

He discovered that integrins control cellular differentiation, and identified a molecular pathway linking integrins with tissue-specific gene expression. His laboratory also revealed that cell-matrix interactions determine apoptosis by controlling Bax trafficking between cytosol and mitochondria. Charles’ group further discovered that integrins determine the orientation of cellular polarity in breast, and that this occurs via endocytosis of apical components away from cell-matrix adhesions.

Now Charles is evolving completely novel areas of research on cell-matrix interactions. He is determining how the micro-mechanics of breast tissue has a central role in starting cancer in women, as well as the links between cell-matrix adhesion and circadian clocks in breast biology. He is also investigating how the small GTPase, Rac1, contributes to breast development and cancer.  

In public engagement, Charles has supervised work experience for A Level students, delivered biology activities at local schools, and participated over many years in science exhibitions & events for children in the Faculty of Life Sciences, at the Whitworth Art Gallery, and at the Manchester Museum.

Raised mammographic density: causative mechanisms and biological consequences.

Sherratt MJ, McConnell JC, Streuli CH.

Breast Cancer Research 2016 18:45. doi: 10.1186/s13058-016-0701-9

The integrin-mediated ILK-Parvin-aPix signalling axis controls differentiation in mammary epithelial cells.

Rooney N, Wang P, Brennan K, Gilmore AP, Streuli CH.

J Cell Physiol. 2016 Mar 27. doi: 10.1002/jcp.25390.   

Increased peri-ductal collagen micro-organization may contribute to raised mammographic density.

McConnell JC, O'Connell OV, Brennan K, Weiping L, Howe M, Joseph L, Knight D, O'Cualain R, Lim Y, Leek A, Waddington R, Rogan J, Astley SM, Gandhi A, Kirwan CC, Sherratt MJ, Streuli CH.

Breast Cancer Res. 2016 Jan 8;18(1):5. doi: 10.1186/s13058-015-0664-2.

Cellular microenvironment controls the nuclear architecture of breast epithelia through ß1-integrin.

Maya-Mendoza A, Bartek J, Jackson DA, Streuli CH.

Cell Cycle. 2016 Feb;15(3):345-56. doi: 10.1080/15384101.2015.1121354.

Building breast tissue to help understand breast cancer.

Wood AM, Streuli CH. 2016.

BioMed Central Blog On-Medicine. http://blogs.biomedcentral.com

Integrin a4ß1 controls G9a activity that regulates epigenetic changes and nuclear properties required for lymphocyte migration.

Zhang X, Cook PC, Zindy E, Williams CJ, Jowitt TA, Streuli CH, MacDonald AS, Redondo-Muñoz J.

Nucleic Acids Res. 2016. 44:3031-44. doi: 10.1093/nar/gkv1348.

The MEF2-HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro.

Clocchiatti A, Di Giorgio E, Viviani G, Streuli C, Sgorbissa A, Picco R, Cutano V, Brancolini C.

J Cell Sci. 2015 Nov 1;128(21):3961-76. doi: 10.1242/jcs.170357.

The Immunology of Breast Development.

Travis MA, Streuli CH.

Dev Cell. 2015 Sep 14;34(5):487-8. doi: 10.1016/j.devcel.2015.08.015.

Integrins and epithelial cell polarity.

Lee, J. and Streuli, C.H. (2014).

J Cell Sci. 127, 3217-25.

Immortalised breast epithelia survive prolonged DNA replication stress and return to cycle from a senescent-like state.

Maya-Mendoza, A., Merchut-Maya, J., Bartkova, J., Bartek, J., Streuli, C.H.*, Jackson D.A*. (2014).

Cell Death and Disease. 5: e1351.

A role for ß3-integrins in linking breast development and cancer.

Ucar, A. and Streuli, C.H. (2014).

Dev Cell. 30, 251-2.

Phosphorylation of the pro-apoptotic BH3-only protein Bid primes mitochondria for apoptosis during mitotic arrest.

Wang, P., Lindsay, J., Owens, T.W., Mularczyk, E.J., Warwood, S., Foster, F., Streuli, C.H., Brennan, K. and Gilmore, A.P. (2014).

Cell Rep. 7, 661-71.

FGF ligands of the postnatal mammary stroma regulate distinct aspects of epithelial morphogenesis.

Zhang, X., Martinez, D., Koledova, Z., Qiao, G., Streuli, C.H. and Lu, P. (2014).

Development. 141, 3352-62.

An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium.

Akhtar N, Streuli CH. (2013).

Nat Cell Biol. 15, 17-27.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.

Eccles SA et al. (2013).

Breast Cancer Res. 15, R92.

Integrins in breast biology.

Glukhova, M. and Streuli, C.H. (2013).

Curr Opin Cell Biol. 25, 633-41.

Signalling pathways linking integrins with cell cycle progression.

Moreno-Layseca, P. and Streuli, C.H. (2013).

Matrix Biol. pii: S0945-053X(13)00140-6.

Inhibitor of Apoptosis proteins: promising targets for cancer therapy.

Owens, T.W., Gilmore, A.P., Streuli, C.H. and Foster, F.M. (2013).

Journal of Carcinogenesis and Mutagenesis S14-004.

Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming.

Schellenberg, B., Keeble, J.A., Walker, S., Owens, T.W., Foster, F., Tanianis-Hughes, J., Brennan, K., Streuli, C.H. and Gilmore, A.P. (2013).

Mol Cell. 49, 959-71.

Cell adhesion in cancer. In: The Molecular Biology of Cancer, 2nd edition (Ed Pelengaris S, Kahn M).

Streuli, C.H. (2013).

Wiley-Blackwell Publishing Inc, Chichester, UK. 383-409.

Specific ß-containing integrins exert differential control on proliferation and 2D collective cell migration in mammary epithelial cells.

Jeanes, A.I., Wang, P., Moreno-Layseca, P., Paul, N., Cheung, J., Tsang, R., Akhtar, N., Foster, F.M., Brennan, K. and Streuli, C.H. (2012).

J. Biol. Chem. 287, 24103-12.

The RhoA-Rok-myosin II pathway is involved in extracellular matrix mediated regulation of prolactin signaling in mammary epithelial cells.

Du J-Y, Chen M-C, Hsu T-C, Wang J-H, Brackenbury L, Lin T-H, Yang Y, Streuli CH, Lee Y-J. (2011)

Journal of Cellular Physiology. Jun 15. doi: 10.1002/jcp.22886.

Cellular microenvironment influences the ability of mammary epithelia to undergo cell cycle.

Jeanes, A. I., Maya-Mendoza, A., & Streuli, C. H. (2011).

PloS One, 6(3), e18144. doi:10.1371/journal.pone.0018144.

How integrins control mammary epithelial differentiation: A possible role for the ILK-PINCH-Parvin complex.

Rooney, N., & Streuli, C. H. (2011).

FEBS Letters. doi:10.1016/j.febslet.2011.05.014.

Life and the matrix.

Streuli, C.H. (2012).

Development 139, 4498-4499.

The C’-terminus of talin links integrins to cell cycle progression.

Wang P, Ballestrem C, Streuli CH. (2011).

J. Cell Biol. 195, 499-513.

Bridgewater RE, Streuli CH, Caswell P. 2017. Extracellular matrix promotes clathrin-dependent endocytosis of prolactin and STAT5 activation in differentiating mammary epithelial cells. Scientific Reports 7:4572. doi:10.1038/s41598-017-04783-6

Moreno-Layseca P, Ucar A, Sun H, Wood A, Olabi S, Gilmore AP, Brennan B, Streuli CH. 2017. The requirement of integrins for breast epithelial proliferation. European Journal of Cell Biology. 96:227-239. doi: 10.1016/j.ejcb.2017.03.005

Yang N, Williams J, Pekovic-Vaughan V, Wang P, Olabi S, McConnell J, Gossan N, Hughes A, Cheung J, Streuli CH, Meng Q-J. 2017. Cellular mechano-environment regulates the mammary circadian clock. Nature Communications. 8:14287. doi: 10.1038/ncomms14287

Raphael B, Khalil T, Workman V, Smith A, Brown CP, Streuli C, Saiani A, Domingos M. 2017. 3D cell bioprinting of self-assembling peptide-based hydrogels. Materials Letters. 190:103-106. doi: 10.1016/j.matlet.2016.12.127

Wood A, Sun H, Williams J, Brennan K, Gilmore AP, Streuli CH. 2017. 3D breast culture models: New culture models for analysing breast development and function. In ’Organoids and mini-organs’. Elsevier. In Press.

Streuli CH. 2016. Integrins as architects of cell behaviour. Molecular Biology of the Cell. 27:2885-2888. doi:10.1091/mbc.E15-06-0369

Akhtar N, Li W, Mironov A, Streuli CH. 2016. Rac1 controls both the secretory function of the mammary gland and its remodeling for successive gestations. Developmental Cell. 38:522-535. doi: 10.1016/j.devcel.2016.08.005

Koledova Z, Zhang X, Streuli CH, Clarke RB, Klein OD, Werb Z, Pengfei Lu. 2016. SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling. Proceeding of the National Academy of Sciences, USA. 113:E5731-E5740. doi: 10.1073/pnas.1611532113

Walker S, Foster F, Wood A, Owens T, Brennan K, Streuli CH, Gilmore AP. 2016. Oncogenic activation of FAK drives apoptosis suppression in a 3D-culture model of breast cancer initiation. Oncotarget. 7:70336-70352. doi: 10.18632/oncotarget.11856

Blakeman V, Williams J, Meng QJ, Streuli CH. 2016. Circadian clocks and breast cancer. Breast Cancer Research. 18:89. doi: 10.1186/s13058-016-0743-z

Martin K, Pritchett J, Llewellyn J, Mullan A, Athwal V, Dobie R, Harvey E, Zeef L, Farrow S, Streuli C, Henderson N, Friedman S, Hanley N, Hanley KP. 2016. PAK proteins and YAP-1 signaling downstream of integrin beta-1 in myofibroblasts promotes liver fibrosis. Nature Communications. doi:10.1038/ncomms12502

Research topic - How cell-matrix adhesion controls breast biology

The breast is an organ that contains an intricate network of epithelial ducts and associated alveoli, which are embedded within a stromal connective tissue made up of extracellular matrix. The alveoli are milk factories and the ducts are tubes that transport milk to the nipples. Both require the matrix to develop properly, and for the breast to work as a secretory organ. Understanding the molecular basis for how cell-matrix adhesion controls breast biology underpins the research in our laboratory.

The way that epithelia form and function, and become deregulated in disease, is a fundamental biological question of our time. My research focusses on how cells translate the language of their extracellular matrix into the responses that underpin tissue behaviour. We study the breast because it is an excellent system for uncovering basic principles of cell and developmental biology, and because our work can reveal new targets for treating breast cancer. We’d like to know how the cellular microenvironment controls breast epithelial cell function and how it influences rhythmic variations in everyday circadian cycles. We are also determining how the matrix impacts on the susceptibility of breast epithelia to become cancerous. Importantly, the molecular principles that define how the epithelia of breast tissue function will reveal mechanisms underpinning the biology of all epithelia.

Sometimes, cells in ducts or alveoli can become cancerous. One of the central problems in cancer is that cell adhesion to the extracellular matrix changes. Either the matrix stiffens, or the cell’s integrin receptors adjust subtly, or alternatively the intracellular enzymes that integrins control become mutated. The cells then don’t know how to behave properly. For these reasons, we are also determining how altered cell-matrix interactions are involved with the onset of breast cancer in susceptible patients.

Current main scientific interests

1: Differentiation and breast biology. Over many years we have studied the lactation programme, demonstrating a key role for the cellular microenvironment in breast function. Using 3D-culture models, and cells with altered gene expression, as well as gene knockouts in vivo, we discovered that integrin receptors and their downstream signalling molecules, are crucial for the formation of a lactating tissue that makes milk. Altered cell-matrix interactions and integrins also have central roles in the onset and progression of breast cancer, leading us to pursue new medically-related research areas: i) With Dr Andrew Gilmore, we are exploring how the signals derived from extracellular matrix can alter normal breast cell behaviour to cause cancer. ii) With Dr Marco Domingos and engineering colleagues, we are developing 3D-bio-printing methods to contribute to those studies. iii) With Dr Ahmet Ucar, we are studying the integrin-signalling protein Rac1, focussing on its role in both normal and cancerous breast tissue. iv) In work with Dr Pat Caswell, we are looking at novel ways that prolactin signalling is controlled.

2: Mammographic density and breast cancer risk. High mammographic density, and the consequent stiff tissue microenvironment provided by the extracellular matrix, is one of the greatest risk factors for breast cancer. However the mechanisms by which ‘stiffness’ contributes to cancer are not understood at all. In collaboration with Drs Mike Sherratt, Rob Clarke and clinical colleagues, our research is examining how breasts with different mammographic densities are formed. We are also investigating how ‘mechanotransduction’ pathways control the way that epithelial cells behave and how they might trigger breast cancer in post-menopausal women. In detail, we are delving into the biophysics of breast density in several ways. These include: i) looking at breast structure, molecular architecture and protein/RNA/DNA composition, and determining how this differs between normal and tumour areas in women with different density breasts; ii) characterising the relationship between global mammographic density, local tissue structure/mechanics, and X-ray attenuation in cancerous and non-cancerous breasts, and how this leads to different densities; and iii) exploring breast micro-structure at the atomic level to determine how matrix architecture affects X-ray attenuation. iv) We also trying to understand how the breast epithelium influences stromal structure and density.

3: Circadian clocks in the breast. In collaboration with Prof Qing-Jun Meng, we showed that there are >600 genes in the breast that are expressed with circadian time-keeping, but that clock amplitude diminishes in ageing, probably due to stiffening of the stromal matrix. Mechanotransduction suppresses clocks through a talin-vinculin-Rho pathway that controls the actin cytoskeleton. Moreover, genetically deleting clock genes prevents stem cell survival, providing a circadian link between the matrix and breast stem cells. i) Now we aim to determine the role of clocks in normal breast development and lactation, and to ask whether clocks are required for ductal and lobular mammary epithelial function for the duration of life. ii) Since clocks are strongly regulated by stromal stiffness, we are examining whether high mammographic density contributes to breast cancer by altering the circadian system. iii) Clocks are reduced during ageing and are strongly linked to breast cancer, so we are establishing whether restoring normal clocks in breast cancer cells can rescue inappropriate growth. iv) Finally we’d like to understand the molecular links between a stiff stroma and deregulated clocks, so we’re dissecting the roles of known stiffness-regulators of gene expression including Nesprin/Sun proteins, and the Yap/Taz and the MRTF/SRF transcriptional control pathways in breast biology.

Akhtar N, Streuli CH. 2013. An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium. Nature Cell Biology 15:17-27.

Wang P, Ballestrem C, Streuli CH. 2011. The C terminus of talin links integrins to cell cycle progression. Journal of Cell Biology 195:499-513.

Akhtar, N., Marlow, R., Lambert, E., Schatzmann, F., Lowe, E. T., Cheung, J., Katz, E., Li, W., Wu, C., Dedhar, S., Naylor, M. J., and Streuli, C. H. (2009) Molecular dissection of integrin signalling proteins in the control of mammary epithelial development and differentiation, Development 136, 1019-27.

Naylor, M. J., Li, N., Cheung, J., Lowe, E. T., Lambert, E., Marlow, R., Wang, P., Schatzmann, F., Wintermantel, T., Schuetz, G., Clarke, A. R., Mueller, U., Hynes, N. E., and Streuli, C. H. 2005. Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation, Journal of Cell Biology 171, 717-28.

Runswick SK, O'Hare MJ, Jones L, Streuli CH, Garrod DR. 2001. Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nature Cell Biology 3:823-830.

Gilmore A. Metcalfe AD, Romer LH, Streuli CH. 2000. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localisation. Journal of Cell Biology 149:431-445.

Farrelly N, Lee Y-J, Oliver J, Dive C, Streuli CH. 1999. Extracellular matrix regulates apoptosis in the mammary gland through a control on insulin signalling. Journal of Cell Biology 144:1337-1348.

Pullan S, Wilson J, Metcalfe A, Edwards GM, Goberdhan N, Tilly J, Hickman JA, Dive C, Streuli CH. 1996. Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. Journal of Cell Science 109:631-642.

Streuli CH, Bailey N, Bissell MJ. 1991. Control of mammary epithelial differentiation: the separate roles of cell-substratum and cell-cell interaction. Journal of Cell Biology 115:1383-1395.

Streuli CH, Griffin BE. 1987. Myristic acid is coupled to a structural protein of polyoma virus and SV40. Nature 326:619-621.

Yang N, Williams J, Pekovic-Vaughan V, Wang P, Olabi S, McConnell J, Gossan N, Hughes A, Cheung J, Streuli CH, Meng Q-J. 2017. Cellular mechano-environment regulates the mammary circadian clock. Nature Communications. 8:14287. doi: 10.1038/ncomms14287

Akhtar N, Li W, Mironov A, Streuli CH. 2016. Rac1 controls both the secretory function of the mammary gland and its remodeling for successive gestations. Developmental Cell. 38:522-535. doi: 10.1016/j.devcel.2016.08.005