Reversing Epithelial Mesenchymal Plasticity with Eribulin to Enhance Therapy Response

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 reverse epithelial mesenchymal transition (EMT) (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 prior to 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.

Research activities

We will assess whether prior treatment of breast cancer cell lines and patient-derived tumouroids in 3-dimensional cultures with eribulin will sensitise them to subsequent treatment with other non-EMT inducing drugs. We have already seen EMT like changes after EMT-promoting neoadjuvant therapy, which were not seen in data from the Neo-eribulin trial (6), collaborative with SOLTI. We will assess drug response (proliferation analysis) and EMT status (immunofluorescence and quantitative PCR) in human breast cancer cell lines and patient-derived organoids. If time permits, we will further examine immune-oncological endpoints, since EMP has been implicated in immune avoidance.

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.
2. To examine the context and scope of eribulin effects on EMT axis phenotype using 3D patient-derived tumouroids.
3. 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.
4. (Stretch Aim) Assess the extent to which immune recognition mediates the impact of EMP on responses and test a combined immunotherapy approach using patient-derived tumouroids.

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 HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2020;21:341-52
2. Williams ED, Gao D, Redfern A, Thompson EW. Controversies around epithelial-mesenchymal plasticity in cancer metastasis. Nat Rev Cancer 2019;19:716-32
3. Redfern AD, Spalding LJ, Thompson EW. The Kraken Wakes: induced EMT as a driver of tumour aggression and poor outcome. Clin Exp Metastasis 2018;35:285-308
4. Terashima M, Sakai K, Togashi Y, Hayashi H, De Velasco MA, Tsurutani J, Nishio K. Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines. Springerplus 2014;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 PJ, Matsui J, Aoshima K, Nomoto K, Oda Y. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 2014;105:1334-42
6. Pascual T, Oliveira M, Villagrasa P, Ortega V, Paré L, Bermejo B, Morales S, Amillano K, López R, Galván P, Canes J, Salvador F, Nuciforo P, Rubio IT, Llombart-Cussac A, Di Cosimo S, Baselga J, Harbeck N, Prat A, Cortés J. Neoadjuvant eribulin in HER2-negative early-stage breast cancer (SOLTI-1007-NeoEribulin): a multicenter, two-cohort, non-randomized phase II trial. NPJ Breast Cancer 2021;7:145

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.

Skills and experience

Ideally the candidate would have a passion for translational cancer research. Experience in cell culture and cell/molecular biology analysis is ideal, but not essential.

In the project, the student will develop:

• 2D and 3D cell culture systems
• cell proliferation analysis – drug responses
• molecular analysis of EMP – Immunocytochemistry and quantitative RT-PCR
• breast cancer-derived 3D tumouroid models for clinically-representative testing.
• immune cell isolation and activation, and assessment of immune responses using ex-vivo patient-derived tumouroids.

Scholarships

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Keywords

• breast cancer
• therapy resistance
• epithelial plasticity

Contact

Contact the supervisor for more information.