Funded PhD Project in stem cells, metabolism and cancer initiation

A MRC DiMeN DTP-funded PhD project (jointly with the groups of Elena Rainero and Zoe Mann) focusing on the links between metabolism, extracellular matrix and embryonic tumour initiation is currently available in the lab of Anestis Tsakiridis, University of Sheffield.

Project description:

Neuroblastoma (NB) is the most common extracranial solid tumor in infants, arising from the oncogenic transformation of trunk neural crest (NC) cells—multipotent embryonic cells that develop into the adrenal gland and sympathetic neurons. Aggressive forms of NB are characterized by chromosomal copy number alterations (CNAs) and overactivation of the MYCN oncogene. Understanding how these genetic changes drive the transition from normal NC cells to their tumorigenic counterparts is essential for developing new therapies. Metabolic reprogramming and cell-extracellular matrix interaction play a key role in both normal NC development and NB progression, yet the precise connection between CNA/MYCN-driven tumor initiation and metabolism remains unclear, hindering the development of more effective treatments for NB.

This PhD project aims to uncover how neuroblastoma (NB)-associated genetic alterations influence the metabolic state and tumorigenic potential of differentiating human trunk neural crest (NC) cells. We have developed an innovative in vitro system that enables precise temporal analysis of the earliest events in NB initiation (Frith et al. 2018; Saldana-Guerrero et al. 2024). This involves the stepwise differentiation of isogenic human embryonic stem cells (hESCs) carrying a doxycycline (Dox)-inducible MYCN overexpression cassette alone or in combination with different NB-relevant CNAs toward trunk NC and their derivatives (= cells-of-origin of NB). The project will employ this model, along with advanced metabolomics, cutting-edge imaging/microscopy techniques, and genetic engineering, to:

Investigate how CNAs and MYCN overexpression impact the metabolic state of human trunk NC cells.
Examine how the extracellular matrix shapes metabolism in both normal and mutant trunk NC cells.
Identify key molecular drivers of CNA/MYCN-induced metabolic reprogramming in trunk NC cells.
The findings of the project will shed light on the metabolic mechanisms underlying NB initiation, offering potential new therapeutic insights.

Funding Notes
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here.

Studentships commence: 1st October 2025

Closing date: Friday, December 13, 2024

To apply see here.