Deciphering the dynamic-plasticity and heterogeneity of cancer-associated fibroblasts

Introduction

Cancer-associated fibroblasts (CAFs) are one of the most abundant and versatile cell types in the tumour microenvironment (TME), where they crosstalk with stromal cells and actively participate in tumour development. Because of their assumed pro-tumourigenic functions, CAFs have long been considered an attractive therapeutic target.

CAF Subpopulations

However, recent evidence indicates that multiple CAF subpopulations showing inflammatory, myofibroblastic, vascular, antigen-presenting, and immunosuppressive phenotypes co-exist within the same tumour. Some of these subpopulations promote tumour growth, while others restrict it, making their targeting challenging.

Research Gaps

How CAFs change dynamically as cancers evolve, and how this may affect the overall tumour heterogeneity, remains unaddressed.

Project Goals

Therefore, the main goal of DynamHet is to elucidate the origin and evolution of CAF heterogeneity and to decipher the mediators and mechanisms that regulate CAF plasticity as the tumour advances. This is crucial for the development of effective therapies aimed at reprogramming CAFs towards therapeutically favourable phenotypes and will constitute a great breakthrough in the field of oncology.

Specific Aims

Hence, DynamHet aims to:

1. Decipher the origin of CAF heterogeneity by performing clonal tracing and by generating and characterising CAF subtypes starting from human induced pluripotent stem cells.
2. Dissect CAF-TME crosstalk by generating 3D patient-derived organoids and spheroids and by analysing their secretome and transcriptomic profiles using high throughput technologies and computational analysis.
3. Reprogramme CAFs by genetic manipulation in favour of therapeutically advantageous subpopulations as a novel therapeutic approach.

Conclusion

DynamHet is an ambitious and feasible project that stands as a pioneer in the new concept of deciphering the origin and reprogramming the dynamic heterogeneity of CAFs towards the development of innovative precision medicine approaches in cancer.