Tumour Progression and Heterogeneity Laboratory

Laboratory Overview

Metastasis, the spread of cancer cells beyond their primary site, is the major cause of death for people with breast cancer. To optimize the treatment of patients with metastatic disease, we need to identify and target the cancer cells that are responsible for cancer progression. These cells are known as Metastasis Initiating Cells (MICs). We know that each cancer cell within a tumour has a unique genomic profile. The Tumour Progression and Heterogeneity laboratory aims to identify the most aggressive clones responsible for cancer progression, and to characterise their biological features, in order to propose new treatments for patients with recurrent disease.

We seek to Track and Treat the cancer cells present in patients’ tissues by using lineage tracing, as well as sequencing technologies, to determine the molecular mechanisms responsible for the dissemination of cancer cells to various organs, and resistance to current therapies.

‘The heterogeneity of local tumours and distant metastases needs to be taken into consideration for the complete eradication of the most aggressive breast cancer clones.’ Dr Delphine Merino, Head, Tumour Progression & Heterogeneity Laboratory
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Our focus

Isolation and characterisation of circulating tumour cells

Liquid biopsies, which capture circulating tumour cells and cell-free DNA in the bloodstream, are a useful, non-invasive, way of monitoring tumour spread and drug response. Our laboratory proposes to study the diversity and biological properties of cancer cells captured in blood, in order to improve the diagnosis of patients, predict drug response and, in the longer term, develop cancer treatments that are personalised to a patient’s specific cancer.

Follow tumour progression using lineage tracing

Each cell collected from a patient’s tumour can be labelled with fluorescent or genetic tags, allowing us to determine which subclones present in the tumour contribute to metastasis, organ specificity and drug-resistance. We are particularly interested in the effect of different microenvironments or ‘niches’ on the survival of cancer cells and the progression of disease.

Test new drugs in advanced models of metastatic breast cancer

Our laboratory is interested in developing ways to test the effect of various drugs on the survival of circulating tumour cells or metastasis. In particular, we will focus on testing the effect of new targeted therapies on metastatic progression.

 

Quick facts

Metastatic disease

Some cancer cells have the ability to spread in the body. They can invade locally, to nearby lymph nodes, to the vasculature, and distant organs. This process is called ‘metastasis’. The mechanisms by which cells are able to adapt to different microenvironment is still unknown, but it appears that only a few cells from a tumour will successfully grow in distant organs and cause symptoms and pain.

Tumour Heterogeneity

Different tumour cells present in a given tumour can show distinct phenotypic profiles such as gene expression, proliferation, and metastatic potential.

Lineage tracing

Lineage tracing is a labelling tool allowing the identification of all offspring of a single cell or a group of cells.

Targeted cancer therapies

Targeted cancer therapies are drugs that specifically block the proliferation, survival or invasiveness of cancer cells. 

  1. Merino, D.*, Whittle J.R.*, Vaillant F.*, Serrano A., Gong J.N., Maragno, A.L., Chanrion M., Schneider E., Pal P., Giner G., Li X., Dewson G., Gräsel J., Lalaoui N., Segal D., Herold M.J., Huang D., Smyth G.K., Geneste O., Lessene G., Visvader J.E., Lindeman G.J. Synergistic action of the MCL-1 inhibitor S63845 in preclinical models of triple negative and HER2-amplified breast cancer. Science Translational Medicine. 2017. 2;9(401); *Co-authors
  2. Merino, D., Pal, P., and Papenfuss, A.T., Elementary – breast cancer culprits leave their signatures on the double helix. Cell Death Differ, 2016, 23, 1577-1578
  3. Merino, D.*, Lok S.W.*, Visvader J.E., and Lindeman G.J., Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer. Oncogene, 2016. 35, 1877-188. *Equal contribution
  4. Merino, D.*, Best S.A*, Asselin-Labat M.L., Vaillant F., Pal B., Dickins R.A., Anderson R.L., Strasser A., Bouillet P., Lindeman G.J. and Visvader J.E. Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. Oncogene 2015. 34, 3926-3934. *Equal contribution
  5. Khaw, S.L*, Merino, D.*, Anderson, M.A., Glaser, S.P., Bouillet, P., Roberts, A.W., and Huang, D.C. Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199.Leukemia, 2014. 28 (6), 1207-1215. *Equal contribution
  6. Herold, M.J., Stuchbery, R., Merino, D., Willson, T., Strasser, A., Hildeman, D., and Bouillet, P. Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice. Cell Death & Disease 2014. 5 (10), e1446.
  7. Vaillant, F*, Merino, D.*, Lee, L., Breslin, K., Pal, B., Ritchie, M.E., Smyth, G.K., Christie M., Phillipson, L.J., Burns, C.J., Mann, G.B., Visvader, J.E. and Lindeman G.J. (2013). Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer. Cancer Cell, 2013. 24 (1), 120-129. *Equal contribution
  8. Merino, D.*, Khaw, S.L.*, Glaser, S.P., Anderson, D.J., Belmont, L.D., Wong, C., Yue, P., Robati, M., Phipson, B., Fairlie, W.D., et al. (2012). Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood, 2012. 119 (24), 5807-5816. *Equal contribution
  9. Clybouw, C.*, Merino, D.*, Nebl, T., Masson, F., Robati, M., O'Reilly, L., Hubner, A., Davis, R.J., Strasser, A., and Bouillet, P. Alternative splicing of Bim and Erk-mediated Bim(EL) phosphorylation are dispensable for hematopoietic homeostasis in vivo. Cell Death Differ 2012. 19:1060-1068. *Equal contribution


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