RNA Dynamics in Cancer

Our Working Hypothesis

How diet shapes the epitranscriptome to modulate cancer cell behaviour

 

Tumour progression and metastasis depend on how well cancer cells can adapt their metabolism and change their behaviour in response to their environment. Diet plays a major role in this process by reshaping the way cancer cells function at a molecular level.

The diagram to the right highlights key research questions we’re tackling to understand how diet affects the epitranscriptome—the chemical modifications on RNA that control protein production in cells.

These modifications are crucial for helping cancer cells switch states, such as from growing rapidly to becoming motile and invasive, a key step in metastasis. The shift from using glucose and amino acids to relying on fatty acids for energy reflects how cancer cells adapt their metabolism during these transitions.

Our goal is to figure out how specific dietary factor changes to the epitranscriptome enable shifts in cancer cell behaviour.

Research areas

Our lab focuses on how diet impacts the course of breast cancer progression by modulating mRNA translation.  To this end, we use xenotransplantation models and multimodal molecular profiling techniques, combined with diverse bioinformatics approaches, centred around RNA biology (i.e., Ribo-seq, RNA-seq, Nanopore-seq).  We have discovered that cells initiating metastasis rewire their RNA modifications landscape to synthesize proteins necessary for energy production and dissemination from primary tumours. We are now looking at how these RNA modifications can be reprogrammed by certain nutrients in diet to affect tumour growth, metastasis and patient survival, and how we can use these vulnerabilities to improve cancer treatments.

 

Mapping the diet-induced epitranscriptome in cancer cells

Diet has emerged as a significant environmental factor influencing cancer progression, yet the specific dietary compounds driving these effects remain poorly understood. Pre-clinical studies have shown that palmitic acid-enriched diets can promote cancer dissemination in mice.

Determine the functional impact of the epitranscriptome on tumour cell states

Our previous work established that the mitochondrial m5C modification is critical for maintaining metastatic-initiating populations in the primary tumour. By leveraging CRISPR-based screening, in-vivo validation, and advanced RNA sequencing technologies, my team aims to identify the key RNA modifying regulators responsible for cancer cell state transition.

The molecular control of the epitranscriptome over the cancer cell proteome

RNA modifications are pivotal regulators of RNA function because they affect the stability and/or the affinity of the RNA target. It ultimately controls globally or specifically protein synthesis. My team uses methods such as ribosome profiling, and proteomic analyses in CRISPR knock-out models to unravel the mechanisms by which the epitranscriptome drives proteomic changes during cancer cell state transitions.

Mapping the diet-induced epitranscriptome in cancer cells
Determine the functional impact of the epitranscriptome on tumour cell states
The molecular control of the epitranscriptome over the cancer cell proteome

A note from the Group Leader – Sylvain Delaunay

My team and I are fortunate to be part of a collaborative and innovative scientific community at the CRUK Manchester Institute. By working closely with researchers and clinicians, we ensure our discoveries address patient needs and have the potential to be translated into effective treatments.

Our group focuses on understanding the role of RNA modifications in cancer biology. Using advanced experimental approaches, we aim to uncover new insights that can transform cancer research and guide the development of novel therapies.

Meet the group

Photo of Junior Group Leader Sylvain Delaunay
Sylvain Delaunay

Junior Group Leader

Katie Stott

Senior Scientific Officer

All Institute Publications

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https://doi.org/10.1186/s12943-024-02157-x

The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer

12 November 2024

Institute Authors (1)

Amaya Viros

Labs & Facilities

Genome Editing and Mouse Models

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Research Group

Skin Cancer & Ageing

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https://doi.org/10.1186/s13045-024-01610-0

The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency

8 October 2024

Institute Authors (6)

Georges Lacaud, Mathew Sheridan, Michael Lie-a-ling, Liam Clayfield, Jessica Whittle, Jingru Xu

Research Group

Stem Cell Biology

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/wp-content/uploads/2024/11/Annual-Report-2023.pdf

2023 Annual Report

13 September 2024

https://doi.org/10.1126/science.adh7954

Vitamin D regulates microbiome-dependent cancer immunity

25 April 2024

Institute Authors (1)

Evangelos Giampazolias

Research Group

Cancer Immunosurveillance

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https://doi.org/10.1038/s41684-024-01363-w

Streamlining mouse genome editing by integrating AAV repair template delivery and CRISPR-Cas electroporation

10 April 2024

Institute Authors (1)

Natalia Moncaut

Labs & Facilities

Genome Editing and Mouse Models

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https://www.biorxiv.org/content/10.1101/2023.12.13.568969v1

A novel human model to deconvolve cell-intrinsic phenotypes of genetically dysregulated pathways in lung squamous cell carcinoma

14 December 2023

Institute Authors (3)

Carlos Lopez-Garcia, Caroline Dive, Anthony Oojageer

Research Group

Translational Lung Cancer Biology

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