Study level

  • Master of Philosophy
  • Honours

Faculty/School

Faculty of Health

School of Biomedical Sciences

Topic status

We're looking for students to study this topic.

Research centre

Supervisors

Associate Professor Laura Bray
Position
Principal Research Fellow
Division / Faculty
Faculty of Engineering
Dr Brett Hollier
Position
Senior Research Fellow
Division / Faculty
Faculty of Health
Professor Rik Thompson
Position
Professor of Breast Cancer Research
Division / Faculty
Faculty of Health
Associate Professor Elizabeth Williams
Position
Head, Tumour Models
Division / Faculty
Faculty of Health

Overview

Epithelial mesenchymal plasticity (EMP) is a highly regulated and powerful cellular process that is fundamental in embryonic development (1), which is hijacked by cancer cells for metastatic progression and therapy resistance in epithelial cancers (2). Eribulin is a microtubule-inhibiting cancer drug discovered in sea sponges and approved for 3rd line therapy in metastatic breast cancer, which was shown to block EMP (3).

We hypothesise that eribulin’s reversal of EMT will sensitise breast cancer cells to other therapies and ultimately improve patient outcomes if used in combination with other breast cancer therapies. Evidence for this has already been seen with in vitro synergism between eribulin and 5-fluor-uracil (5-FU) (4,5). Eribulin has also been shown to cause immune stimulation, consistent with associations between immune-resistance and EMT.

We will assess whether prior treatment of breast cancer cell lines and patient-derived tumouroids in 3-dimensional cultures with eribulin will sensitise to subsequent treatment with other non-EMT inducing drugs. We will assess drug response (proliferation analysis) and EMT status (immunofluorescence and quantitative PCR). We will then assess the impact of eribulin scheduling on responses to therapy in BC model systems in vivo. If time permits, we will further examine immune-oncological endpoints, since EMP has been implicated in immune avoidance.

References:

1.               Yang, J., Antin, P., Berx, G., Blanpain, C., Brabletz, T., Bronner, M., Campbell, K., Cano, A., Casanova, J., Christofori, G., Dedhar, S., Derynck, R., Ford, H. L., Fuxe, J., García de Herreros, A., Goodall, G. J., Hadjantonakis, A. K., Huang, R. J. Y., Kalcheim, C., Kalluri, R., Kang, Y., Khew-Goodall, Y., Levine, H., Liu, J., Longmore, G. D., Mani, S. A., Massagué, J., Mayor, R., McClay, D., Mostov, K. E., Newgreen, D. F., Nieto, M. A., Puisieux, A., Runyan, R., Savagner, P., Stanger, B., Stemmler, M. P., Takahashi, Y., Takeichi, M., Theveneau, E., Thiery, J. P., Thompson, E. W., Weinberg, R. A., Williams, E. D., Xing, J., Zhou, B. P., and Sheng, G. (2020) Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 21, 341-352

2.               Williams, E. D., Gao, D., Redfern, A., and Thompson, E. W. (2019) Controversies around epithelial-mesenchymal plasticity in cancer metastasis. Nat Rev Cancer 19, 716-732

3.               Redfern, A. D., Spalding, L. J., and Thompson, E. W. (2018) The Kraken Wakes: induced EMT as a driver of tumour aggression and poor outcome. Clin Exp Metastasis 35, 285-308

4.               Terashima, M., Sakai, K., Togashi, Y., Hayashi, H., De Velasco, M. A., Tsurutani, J., and Nishio, K. (2014) Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines. Springerplus 3, 417

5.               Funahashi, Y., Okamoto, K., Adachi, Y., Semba, T., Uesugi, M., Ozawa, Y., Tohyama, O., Uehara, T., Kimura, T., Watanabe, H., Asano, M., Kawano, S., Tizon, X., McCracken, P. J., Matsui, J., Aoshima, K., Nomoto, K., and Oda, Y. (2014) Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 105, 1334-1342

Specific Aims

    Specific Aims:

  1. To examine the context and scope of eribulin effects on EMT axis phenotype using well characterized human breast cancer cell lines with differential EMT potential and 3D patient-derived tumouroids
  2. To correlate eribulin effects pre- and post-treatment on the EMP phenotypes seen in Aim 1 with assessment of sensitivity to clinically-relevant therapeutics in vitro using cell lines and patient-derived tumouroids.
  3. Determine the extent to which immune recognition mediates the impact of EMP on responses and test a combined immunotherapy approach using patient-derived tumouroids.

Approaches/skills and techniques

2D and 3D cell culture systems

Cell proliferation analysis – drug responses

Molecular analysis of EMP – Immunocytochemistry and quantitative RT-PCR

Breast cancer metastasis-derived 3D tumouroid models for clinically-representative testing.

In vivo testing in NSG mice with breast cancer cell lines and possibly also one PDX models

Immune cell isolation and activation, and assessment of immune responses using ex-vivo patient-derived tumouroids

Outcomes

Observations of improved therapy responses to chemotherapeutic drugs when given in a sequence rationalised on epithelial mesenchymal plasticity. This has clinical relevance and will be used to support proposals for neoadjuvant clinical trials in patients. Immune stimulation studies may open the door to enhanced immunotherapy.

Required skills and experience

Cell culture and cell / molecular biology analysis ideal, but not essential.

Keywords

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