Transcriptional regulation of blood and lymphatic vessels

Transcription factor control of vascular development

Associate Professor Francois has a dual research interest in the vertebrate vascular tree.

The first one is in exploring the genetic program responsible for building and regenerating blood and lymphatic vessel networks.

The second is in the pharmacological manipulation of key proteins that act as molecular switches for vessel development in the hope of developing novel drugs for use in the treatment of vascular disorders.

“There are a range of diseases where aberrant formation of lymphatic vessels are at play, including rheumatoid arthritis, lymphoedema and cardiovascular malformation,” said Associate Professor Francois.

“Faulty vasculature also plays a central role in solid tumour metastasis. In each of these conditions, vascular development becomes dysregulated.

Research overview

Using mouse and zebrafish embryos, Associate Professor Francois and his group are researching the key genetic pathways influencing lymphatic vascular development. Gene products of these pathways act through complex protein-protein interactions that control the time and spatial resolution of gene expression, ultimately shaping vascular phenotype. One of the aims of the research is to decipher the code of protein-protein interactions that govern vascular development.

“A section of our research focuses on the ‘druggability’ of transcription factors, the key molecular switches that instruct the development of the vascular tree in the embryo. Transcription factors are notoriously difficult targets that cannot be reached by conventional drug design.”

If Associate Professor Francois’ team can develop molecules that block (or promote) the activity of the transcription factors associated with vascular development, then it would be possible to gain some control over the outgrowth of the vasculature in disease settings.

“Advances in sequencing technology and protein engineering have drastically accelerated research in this field, but there’s still a long way to go to translate research findings into the clinic.

“A multidisciplinary approach applying biochemistry, biophysics, genomics, medicinal chemistry and developmental biology is needed to successfully unlock new therapeutic avenues for vascular disorders,” said Associate Professor Francois.

Research projects

Understanding the mode of action of SOXF transcription factors during vascular development.

This project takes advantage of genomics, proteomics and transgenesis approaches to explore the mode of action of SOXF transcription factor during endothelial cell differentiation in vertebrates.

Pharmaco-modulation of SOXF transcription factors activity to manipulate blood and lymphatic vessels in diseases.

This project aims at developing a novel class of drugs and biologics to modulate the vascular response in the context of solid cancer metastasis.

The birth of the lymphatic vasculature at high cellular resolution.

This project explores how lymphatic endothelial assembles as a functional network in an organ-specific manner in zebrafish and mouse embryonic development

Research training opportunities

Summary of research interests: We identify and characterise key transcriptional pathways that modulate lymphatic vascular development in the mouse embryo. We are interested in translating our discoveries in pre-clinical mouse models of cancer or lymphedema to validate the central role of developmental programs that are re-activated under these pathological conditions. Ultimately we aim to develop a novel class of compounds that will enable the pharmacological management of the lymphatics with the view to probing vascular development or setting up the basis for drug development. We use a pipeline of assays ranging from in vitro analysis (fluorescence polarisation, cell-based assays) to in vivo mouse models (melanoma xenograft), and collaborate with other IMB scientists and international research groups who are experts in zebrafish biology, medicinal chemistry and in vivo live imaging.

Traineeships, honours and PhD projects include

  • Analysis of the transcriptional network that governs lymphatic endothelial cell fate (mouse genetics)
  • Molecular characterisation of the embryonic pathways re-activated in lymphatics during cancer metastasis(pre-clinical models)
  • Validation of novel molecular targets and assessment of their druggability to develop novel anti-cancer agents
  • Fundamental basis of peripheral sensory perception.

Contact: Associate Professor Mat Francois

+61 7 3346 2494
m.francois@imb.uq.edu.au


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Featured publications

  • Patel, Jatin, Seppanen, Elke J., Rodero, Mathieu, Wong, Ho Yi, Donovan, Prudence, Neufeld, Zoltan, Fisk, Nicholas, Francois, Mathias and Khosrotehrani, Kiarash (2017) Functional definition of progenitors versus mature endothelial cells reveals key SoxF-dependent differentiation process. Circulation, 135 8: 786-805. doi:10.1161/CIRCULATIONAHA.116.024754

  • Fontaine, Frank, Overman, Jeroen, Moustaqil, Mehdi, Mamidyala, Sreeman, Salim, Angela, Narasimhan, Kamesh, Prokoph, Nina, Robertson, Avril A. B., Lua, Linda, Alexandrov, Kirill, Koopman, Peter, Capon, Robert J., Sierecki, Emma, Gambin, Yann, Jauch, Ralf, Cooper, Matthew A., Zuegg, Johannes and Francois, Mathias (2017) Small-molecule inhibitors of the SOX18 transcription factor. Chemistry Chemical Biology, 24 3: 346-359. doi:10.1016/j.chembiol.2017.01.003

  • Overman, Jeroen, Fontaine, Frank, Moustaqil, Mehdi, Mittal, Deepak, Sierecki, Emma, Sacilotto, Natalia, Zuegg, Johannes, Robertson, Avril A. B., Holmes, Kelly, Salim, Angela A., Mamidyala, Sreeman, Butler, Mark S., Robinson, Ashley S., Lesieur, Emmanuelle, Johnston, Wayne, Alexandrov, Kirill, Black, Brian L., Hogan, Benjamin M., De Val, Sarah, Capon, Robert J., Carroll, Jason S., Bailey, Timothy L., Koopman, Peter, Jauch, Ralf, Smyth, Mark J., Cooper, Matthew A., Gambin, Yann and Francois, Mathias (2017) Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice. eLife, 6 . doi:10.7554/eLife.21221

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Engagement and impact

Associate Professor Mat Francois research uses developmental lymphangiogenesis as a model to understand lymphatic vascular dysregulation in disease. Using a strategic collaborative network he has put in place a combination of molecular tools that rely on mouse and zebrafish genetics, tumour models, genomics and biophysics. This multidisciplinary approach allows unprecedented investigation in vascular biology that ranges from in vivo vascular imaging to deep molecular understanding of transcription factor mode of action.

This approach has led to the discovery of the first in class SOX18 small molecule inhibitors and the demonstration of their therapeutic utility in metastatic breast cancers. 

Partners and collaborators

Associate Professor Mat Francois collaborates locally, nationally and internationally.

Academic partners (local and national) include:

  • The Hogan Lab (UQ) – zebrafish genetics and lymphangiogenesis
  • The Gambin Lab (UNSW)- single molecule analysis of SOX interactome
  • The Cooper Lab and the Capon Lab (UQ) – small molecule inhibitor of SOX protein
  • The Harvey Lab (UniSA) – Genomics of lymphatic specific transcription factors.

Academic partners (international) include:

  • The De Val Lab (Oxford) – Regulatory elements of endothelial cells
  • The Carroll Lab (CRUK) – SOXF genomics in vivo.

Industry partners include:

  • Phylogica: phylomers to disrupt transcription factors activity
  • CSL: ARC technology training center on biopharmaceutical innovation.
     

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A/Prof Mat Francois

Associate Professor Mat Francois

Group Leader, Genomics of Development and Disease Division
Investigator, Centre for Rare Diseases Research

  +61 7 3346 2494  
  m.francois@imb.uq.edu.au
  IMB Researcher Profile
  Centre for Cardiac and Vascular Biology


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  Group Leader

  Researchers

  Students

  • Miss Keyi Jiang

    Higher degree by research (PhD) student
    Institute for Molecular Bioscience
  • Miss Alex Mccann

    Higher degree by research (PhD) student
    Institute for Molecular Bioscience
  • Ms Siew Zhuan Tan

    Higher degree by research (PhD) student
    Institute for Molecular Bioscience