Mutations in healthy tissues: a double-edged sword for tissues homeostasis

Introduction

Healthy tissues become progressively populated by clonally expanded cells that have acquired somatic mutations. Often, these mutations modify cancer genes, promoting cell plasticity, self-renewal, and growth, all features known to decline with ageing. Despite being pervasive across tissues and persistent throughout life, only rarely do mutant cells become pathogenic.

Hypothesis

Here we hypothesise that somatic mutations enhance tissue integrity by increasing the fitness of stem/progenitor cells (SPCs) to counterbalance their age-induced decline. Increased SPC fitness at the cellular level increases the fitness at the tissue level, thus preserving the overall tissue regenerative potential.

Research Approach

To test this hypothesis, we propose to investigate the effect of somatic mutations on SPC fitness in solid tissues and blood using complementary and synergistic approaches specific to our teams, bridging the historically distinct fields of evolutionary genetics and stem cell biology.

Methodology

Through the analysis of human tissues and the use of complex mouse models, we will dissect the interactions between mutant SPCs and their niche, at homeostasis and upon insults. We will determine whether the expansion of mutant SPCs over time leads to a progressive decline in SPC diversity, which eventually increases disease risk.

Work Packages

We will adopt a progressive approach:

1. Characterisation of the mutant clone (WP1) and its crosstalk with the niche (WP2) at homeostasis.
2. Testing the response of the mutant clone and niche to physiological (WP3) and pathological (WP4) challenges.
3. Assessing the occurrence of a multiorgan crosstalk conveyed by mutant blood on mutant solid tissues (WP5).

Impact

This study will radically transform our understanding of tissue homeostasis and clarify the relationship between somatic mutations, ageing, and disease. A deeper knowledge of the mechanisms that maintain the homeostatic equilibrium over time is the first step to guide intervention and disease prevention.