Single-cell characterisation of thyroid cell plasticity in cancer and regeneration

Supervisor: Dr. Sabine Costagliola

Cells are not a static entity. Like a chameleon they change their characteristics based on the context and environment. Mostly the change is subtle, like oscillations in response to circadian rhythm. However, sometimes the change is so drastic, that the cell changes its personality, like Jekyll and Hyde, assuming a new identity. Such plasticity is often necessary, like during regeneration when cells need to undergo cell-cycle; but also, often detrimental, like during cancer when the new rogue identity brings the biological system to a breakdown. In this project, you will investigate radical changes in cellular identity imposed during cancer and regeneration and compare and contrast the two situations.

To investigate the role and regulation of cell plasticity, you will utilize the thyroid gland in zebrafish model system. Zebrafish provides a genetically modifiable system with the advantage of live imaging of cell behaviours inside of living animals. The thyroid gland is a simple model of epithelial tissue, similar to skin or intestine. We have recently uncovered plasticity in the thyroid population during homeostasis by showing that the thyroid epithelial cells can be present in different transcriptional states. Your project will expand the study of plasticity to BRAF-induced cancer model and to regeneration upon injury to a subset of the organ.

You will ask the following specific questions:
For cancer:

  1. What is the immediate impact of thyroid identity upon induction of BRAF?
  2. What part of BRAF-induced identity leads to metastasis of an epithelial tissue?
  3. How close is the identity of thyroid epithelial cells that have undergone metastasis to new organs when compared to the original identity?

For regeneration:

  1. Upon injury to the organ, what induces the spared cells to lower their functional identity and enter cell-cycle (thyroid cells are normally non-proliferative)?
  2. What induces the cells to exit cell-cycle and become integrated into the functional unit of the organ? (And why cell-cycle exist is blocked during cancer?)

To answer these questions, you will have access to a wide variety of cutting-edge tools. You will perform single-cell RNA and ATAC-Sequencing to identify changes in identity at transcriptional and epigenetic level. You will utilize spatial transcriptomics to interrogate the environment of the thyroid cells. You will live image cancer development, metastasis, and regeneration using confocal and in-house lightsheet microcopes (Open-SPIM) that are specifically build for long-term zebrafish time-lapse imaging. You will utilize multi-color genetic labelling techniques to trace the behaviour of individual cells. Finally, you will perform CRISPR/Cas9-based gene mutations to perturb genetic networks. Lastly, you will work in a collaborative environment that houses experts in thyroid, development and cancer biology.

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