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Professor Charles Streuli - Mammary Gland Adhesion Group

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, and PhD at the University of Leicester. This was followed by postdoctoral work at the Imperial Cancer Research Fund Laboratories in London, and at the Lawrence Berkeley National Laboratory in California. He was 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 Breakthrough Breast Cancer Research Unit at the University of Manchester in 2009. He was appointed to the position of Director of the Wellcome Trust Centre for Cell-Matrix Research from 2009 to 2014. Charles was elected to become a Fellow of the Society of Biology in 2013.

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 epithelia. By focusing on breast biology, he revealed the central role of integrin adhesion receptors in mammalian cell behavior, providing a general framework for understanding epithelial tissue development and function. He discovered that integrins control epithelial differentiation, identifying a molecular pathway linking them with tissue-specific gene expression. His laboratory also revealed that cell-matrix interactions determines apoptosis by controlling Bax trafficking between cytosol and mitochondrial. Charles’ laboratory also discovered that integrins determine the orientation of epithelial polarity in the breast, and that this occurs via endocytosis of apical components away from cell-matrix adhesions. His laboratory is newly focussing on the small GTPase, Rac1, in both breast development and cancer, and he is developing completely novel areas of research, both into the links between circadian clocks and breast biology, and also how the micro-mechanics of the tissue has a central role in starting breast cancer in people.

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.

The research in our laboratory is focussed on how integrins and cell-matrix interactions control the development and function of epithelial cells. We study the breast because it is an excellent system to uncover basic principles of cell and developmental biology, and because our work can reveal new targets and pathways for treating breast cancer. We’d like to know how the cellular microenvironment controls the way that breast epithelia function and how it influences the rhythmic variations that occur during everyday circadian cycles. We’d also like to determine how matrix impacts on the susceptibility of breast epithelia to becoming cancerous.

How cells translate the language of their extracellular matrix into the responses that define tissue behaviour

Understanding how epithelia form and function, and the mechanisms leading to their deregulation in disease, are fundamental biological questions of our time. My lab has sought to unravel how epithelia work in the mammary gland. We have chosen to study this tissue partly because breast cancer remains the highest in prevalence for females, and partly because mammary development occurs largely after birth making it reasonably amenable to analyse. Moreover the molecular principles that define how the epithelia of breast function reveal many mechanisms underpinning the biology of all epithelia.


The breast is a three-dimensional organ, which contains an intricate network of epithelial ducts and associated alveoli that 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 extracellular matrix to develop properly and for the breast to work as a secretory organ. Understanding how the extracellular matrix functions in breast is the basis of the research in our laboratory.

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 extracellular matrix or the cellular integrin receptors adjust subtly, or the enzymes that they control become mutated, and the cells then don’t know how to behave properly. For these reasons, we are also determining how cell-matrix interactions are involved with the onset of breast cancer in susceptible individuals.

The scientific story

Differentiation and breast biology: Over many years we have studied the lactation programme, and have demonstrated a key role for the cellular microenvironment in breast function. Using 3-dimensional culture models, and cells with altered gene expression or gene knockouts in vivo, we discovered that integrin receptors have a central role in the formation of functional lactating tissue. We also have a keen interest in the signals derived from extracellular matrix that alter normal breast cell behaviour to cause cancer. We are currently studying the integrin-signalling protein Rac, focussing on its role in both normal and cancerous breast epithelia.

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 Dr Mike Sherratt and clinical colleagues, our research is examining how breasts with different mammographic densities are formed, and also how ‘mechanotransduction’ pathways control the way that epithelial cells behave and how they might trigger breast cancer in post-menopausal women.

Circadian clocks in the breast: We have discovered that the breast shows dramatic changes in gene expression over 24-hour ‘circadian’ time periods. We found that mechanical signals from the extracellular matrix control the circadian clock, whereby a stiff microenvironment suppresses the expression of numerous ‘clock’ genes. Indeed, cell-matrix interactions link to the circadian clock via integrin signalling proteins such as vinculin, and the cytoskeleton. We have also discovered that clock genes are centrally involved in determining the behaviour of breast epithelial stem cells, and are therefore crucial for normal development and function of the tissue.

 

Current and Future Projects

  • The role of mechanotransduction on the early stages of breast cancer, in collaboration with Mike Sherratt and Ashu Gandhi
  • How circadian clocks control mammary gland biology, in collaboration with Qing Jun Meng (Nan Yang and Jack Williams)
  • Understanding the role of Rac1 in the growth requirements of breast epithelia, in collaboration with Rob Clarke (Ahmed Ucar)
  • The way that mechanical stiffness determines cell fate in breast cells via integrin signalling, in collaboration with Andrew Gilmore (Tabea Hohensea)
  • How integrin signals control the activity of breast stem cells (Safiah Olabi)
  • Determining the molecular composition of breast epithelial adhesion complexes using proteomic approaches, in collaboration with Martin Humphries and Mark Morgan

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.