Project Reference: TRG27-ECI-AF1

Project title: Spatial mapping of somatic clonal selection and immune pruning in tissue homeostasis

Project outline

Project Overview

As adult tissues age, they become natural mosaics of mutant cell populations (somatic clones) that outcompete their neighbours through Darwinian evolution. While these clonal expansions appear structurally normal, their broader effects on fundamental tissue homeostasis and physiological aging remain unknown. Using novel evolutionary modelling comparing mutation rates in antigenic versus non-antigenic peptides, we uncovered evidence that highly expanded somatic clones in barrier tissues with high mutation burdens (skin, lung, oesophagus) are actively eliminated by the immune system. This suggests that immune surveillance serves an unappreciated, cell-extrinsic quality control function to clear altered cell populations before they disrupt tissue integrity and function.

Methodology and Experimental Approach

To dissect these interactions, this project leverages a mixture of experimental spatial multi-omics and computational apporaches. Our laboratory recently developed a novel spatial profiling method combining single-cell whole-genome sequencing, transcriptomics, and spatial mapping (integrating Slide-Tags and DEFND-seq technologies). The student will apply this laboratory platform alongside bioinformatic analysis to map the spatial architecture of somatic clones within healthy human esophagus samples, determining how clonal expansion drives localised immune activation.

Aims and Fundamental Impact

Core aims include applying our newly developed spatial platform to resolve somatic clones across healthy oesophageal tissue layers, integrating computational modeling to quantify local immune responses surrounding expanded clones versus wild-type niches, and correlating clonal antigenic burden with immune infiltration. This work will elucidate fundamental principles of tissue self-organization, cell competition, and healthy aging.

Principal Supervisor

Dr Alexander Frankell

Email address: amf71@cam.ac.uk

Department / Partner Institute: Oncology / Early Cancer Institute (ECI)

Website: https://frankell-lab.com/

BBSRC strategic theme

Understanding the rules of life