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

Informations projet

DynamHet

N° de convention de subvention: 101077312

DOI

10.3030/101077312

Date de signature de la CE 5 Mai 2023

Date de début 1 Septembre 2023

Date de fin 31 Août 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 775 190,00

Contribution de l’UE

€ 1 775 190,00

Coordonné par

FUNDACIO DE RECERCA CLINIC BARCELONA-INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Spain

Periodic Reporting for period 1 - DynamHet (Deciphering the dynamic-plasticity and heterogeneity of cancer-associated fibroblasts)

Période du rapport: 2023-09-01 au 2026-02-28

Résumé du contexte et des objectifs généraux du projet

Cancer-associated fibroblasts, or CAFs, are one of the most common and flexible types of cells found in the environment around a tumour. They interact with other nearby cells and play an active role in how the tumour grows and behaves. Because they’re thought to help tumours grow, scientists have been interested in targeting them for treatment.

But here’s the catch: recent studies show that CAFs aren’t all the same. In fact, there are several types of them within a single tumour—some that help the tumour grow, and others that actually hold it back. These types include inflammatory, myofibroblastic, vascular, antigen-presenting, and immunosuppressive CAFs. This mix makes it tricky to treat them effectively.

What we still don’t fully understand is how CAFs change over time as the cancer progresses, and how that affects the overall complexity of the tumour. That’s where the DynamHet project comes in.

The goal of DynamHet is to figure out where this CAF diversity comes from, how it evolves, and what controls these changes. This knowledge could help scientists develop better treatments that “reprogram” CAFs to behave in ways that are more helpful for fighting cancer.

To do this, DynamHet will:

- Trace the origins of CAFs by using stem cells and studying how different CAF types develop.
- Explore how CAFs interact with their surroundings using 3D models made from patient samples, and analyze the molecules they produce and their gene activity.
- Genetically tweak CAFs to shift them toward types that are more beneficial for therapy.

In short, DynamHet is a bold and innovative project that could lead to new, more precise ways to treat cancer by understanding and reshaping the behaviour of CAFs.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

On top of invitations to contribute reviews and manuscripts as corresponding author (PMID: 39929812, PMID: 40043738, PMID: 37018128, PMID: 39117110), publications in collaborative studies (PMID: 40820091, PMID: 40754225, PMID: 39057138, PMID: 38563629), and securing new funding opportunities (XXVII Beca FERO Young Investigators 2024, Ramón y Cajal competitive Spanish program RYC2022-036321-I, Ministry of Science and Innovation of Spain PID2024-160007OB-I00), here are five of the most significant achievements obtained during the first two years of DynamHet:
• Invited speaker at TEDx Spring 2023, organized by ESADE Business School in Barcelona (May 4th, 2023). https://www.youtube.com/watch?v=kcFEp0ar5Xg
Being invited as speaker at a TEDx talk was a unique opportunity to publicly introduce the scientific vision behind my ERC project to a broad and interdisciplinary audience. Through the lens of serendipity, I shared my personal and professional journey into academia, highlighting the unexpected turns and discoveries that shaped my research path. By bridging science, storytelling, and public engagement, the TEDx talk served as a powerful launchpad for my research line and group, amplifying its visibility and societal impact from the very beginning.
• Invited Speaker at the AASLD Annual Meeting, American Association for the Study of the Liver, Boston, USA (November 2023). Being invited as speaker at the American meeting for the Study of the Liver diseases allowed me to present novel insights into the role of CAFs in liver cancer progression and immune modulation, directly aligning with the core objectives of the ERC project, to get international visibility, and to expand my network of collaborations.
• Working Group Member at the Cholangiocarcinoma Foundation 12th Annual Conference, invited as expert leader in tumor microenvironment to define Priority Research Areas and contribute to redact a new CCA Consensus Statement (April 2025, Salt Lake City, Utah, USA). Being invited as a Working Group Member at the CCF meeting is a significant recognition of my expertise in the tumor microenvironment. My participation in this international expert panel allowed me to integrate insights from my ERC-funded research into the strategic planning of future research directions in CCA, ensuring that stromal biology and CAF-targeted approaches are prioritized in the global research agenda. It also provides a unique opportunity to influence clinical and translational frameworks that could accelerate the impact of my project beyond academia.
• Emerging Leader Award 2025, awarded by the European Association for the Study of the Liver (EASL), Amsterdam, Netherlands (May 2025). Being awarded this award is a significant milestone that reinforces the scientific excellence and relevance of my ongoing ERC project. This prestigious recognition highlights my leadership in liver research and acknowledges the impact of my work on the tumor microenvironment, particularly the role of CAFs in liver cancer progression and therapy resistance.
• Invited Preview in Cancer Cell: Stromal barriers to the abscopal effect. Tian TV, Affò S*. Corresponding author. Cancer Cell. 2025 May 12;43(5):810–812. doi: 10.1016/j.ccell.2025.04.008. PMID: 40359907. This invitation to contribute a Preview article in Cancer Cell—one of the most prestigious journals in oncology—represents an international recognition of my scientific leadership and expertise in the physiopathology of cancer-associated fibroblasts. The article explores how stromal components, particularly CAFs, may hinder systemic anti-tumor responses such as the abscopal effect, a concept that aligns closely with the central hypotheses of my ongoing ERC-funded project. This contribution reinforces the relevance and impact of my current research, which aims to unravel the mechanisms by which CAF modulates immune surveillance and therapeutic efficacy.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

While further analysis is needed to confirm the consistency and robustness of our findings, we have already observed promising results that may significantly advance the field. Notably, we were surprised to discover that iPSC-derived primary CAFs exhibit an immunosuppressive phenotype when analyzed using pan-cancer immunosuppressive signatures. This was an unexpected outcome and opens new avenues for understanding CAF-driven immune modulation. These findings will be further explored and validated using recently published datasets and resources (PMID: 40969325, PMID: 41005303, PMID: 39255773).
Another advance that may contribute to the field is our ability to detect which CAF subtypes emerge during tumorigenesis and their correlation with increasing stiffness. This insight could pave the way for early detection and therapeutic targeting of tumors by manipulating CAFs at the initial stages of their appearance, therefore avoiding the generation of an immunosuppressive niche. Such predictive modeling of CAF dynamics represents a step forward in understanding tumor-stroma interactions and could inform the development of novel intervention strategies.
Although these findings were not originally anticipated, they align well with the overarching goals of the project and demonstrate the potential of our integrated experimental and computational approach to uncover new biological mechanisms and therapeutic opportunities.