Harnessing Stromal Fibroblasts to Reduce Resistance and Improve Colon Cancer Therapeutics

Informations projet

antiCAFing

N° de convention de subvention: 101045756

DOI

10.3030/101045756

Date de signature de la CE 8 Août 2022

Date de début 1 Septembre 2022

Date de fin 31 Août 2027

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 999 826,00

Contribution de l’UE

€ 1 999 826,00

Coordonné par

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 1 - antiCAFing (Harnessing Stromal Fibroblasts to Reduce Resistance and Improve Colon Cancer Therapeutics)

Période du rapport: 2022-09-01 au 2025-02-28

Résumé du contexte et des objectifs généraux du projet

Colorectal cancer (CRC) is the most commonly diagnosed cancer and the second cause of cancer death in Europe. CRC patients may be treated with surgery or with systemic treatments including chemo-, targeted or immunotherapy. Despite this spectrum of therapeutic options, refractory tumors and drug resistance are still significant, and represent the most important challenge in CRC treatment. The genetic determinants of response are well-known, but there are still tumors that fail to respond and whose behavior cannot be explained. Tissue composition and non-cancerous cells (i.e. the tumor microenvironment, TME) are important contributors to tumor progression, but their impact in resistance remains poorly understood. Among these, cancer-associated fibroblasts (CAFs) participate in key tumorigenic processes, including matrix remodeling, cancer cell invasion and growth. Importantly, these aggressive CAF phenotypes are controlled by mechanical reprogramming and mechanotransduction pathways. The prominent influence of CAFs in these and other processes suggest that targeting them may represent an innovative alternative for therapeutic intervention that has not been exploited in the clinic, as we still have a limited understanding of the interplay of CAFs and therapy. Revealing the rules that govern CAF-dependent mechanisms of resistance, and identifying novel ways to identify and modulate aggressive CAFs, represents a novel strategy to improve the diagnosis and treatment of cancer.
The overall goal of our project is to systematically dissect how mechanotransduction alters the behavior of CAFs and controls biological processes that influence therapeutic responses in CRC. Specifically, we will investigate how CAFs: (i) contribute to abnormal tumor vascularization and poor anti-cancer drug penetrance; (ii) crosstalk to cancer cells and diminish the effect of targeted chemotherapies; and (iii) alter immune cell composition and influence immunotherapy responses. Moreover, we will also explore whether CAFs with aberrant mechanotransduction present specific epitopes that could be subsequently used for identification and targeted modulation to improve therapeutic responses. Overall, our project will illuminate novel mechanisms whereby TME characteristics influence tumorigenesis and therapeutic responses, and inform the development of refined biomarkers to stratify patients and next generation combinatorial therapies with reduced risk of recurrence.

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

Since the beginning of the project, our work has been focused in assessing how aberrant mechanotransduction in CAFs affects biological processes associated with therapeutic resistance in colorectal cancer (CRC), including:
1. CAFs in abnormal vascularization. CAFs are commonly regarded as components that promote the formation of blood vessels in tumors. But vasculature in tumors is often aberrant (tortuous, compressed, leaky), which negatively affects the penetrance of anticancer drugs. We have generated state-of-the-art microfluidic devices to generate functional vasculature, and assessed the role of CAFs in vascularization. By applying this methodology, we described that CAFs are key mediators of abnormal vasculature and we are starting to uncover the underlying mechanisms and the pathobiological relevance in tumor progression and treatment responses.
2. CAFs in shielding cancer cells from chemotherapy. In-depth characterization of tumors has provided new molecular targets that informed the development of targeted therapeutics and personalized medicine. However, a significant percentage of patients are refractory or stop responding to these treatments. In our project we have generated models of CRC CAF heterogeneity and explored how specific CAF subsets and mechanisms reduce the efficacy of different types of chemotherapies for CRC patients.
3. CAFs in immune suppression. Responses to immunotherapy vary greatly between patients and the underlying causes remain unclear. We postulate that stromal components, rather than intrinsic molecular characteristics of the tumor, are key determinants of immune responses. Using animal and in vitro models, we have investigated how aberrant mechanotransduction in CAFs alters immune cell composition in tumors. Our results suggest that blocking certain pathways in CAFs reduces inmmunosuppresion and makes tumors more susceptible to immunotherapy.
In all these activities we have stablished a clear link between CAFs and processes associated with diminished efficacy of chemo-, targeted and immunotherapies in CRC. Describing the role of mechanotransduction in CAFs in these contexts will provide a new conceptual framework for therapeutic resistance. But selectively identifying (and modulating) CAFs with aberrant mechanotransduction remains challenging. We have established novel methodology based in combinatorial chemistry that will be employed to generate aptamer-based probes that can selectively identify these set of CAFs.

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)

Mechanotransduction in CAFs has been shown to participate in multiple tumoral processes, but how it is related to therapeutic responses is not well characterized. In our projected we have uncovered novel functions associated to fibroblast mechanotransduction in vascularization employing sophisticated organ-on-chip devices. Our unpublished results indicate that CAFs display a series of aberrant properties that lead to the emergence of abnormal non-functional vasculature, and provide an understanding of the underlying molecular mechanisms. These results explain the characteristic phenotypes of tumor-associated vasculature and the particular impact of CAFs, with implications in anti-cancer drug perfusion and efficacy. In addition, we have participated in studies showing how the mechanical properties of the subendothelial extracellular matrix at distant sites influence metastatic success. Our project is also describing how mechanotransduction affects the ability of CAFs to reduce the efficacy of targeted and immune-based therapeutics, and new canning ways to identify particularly aggressive CAFs exploiting the power of aptamer variability through Cell-SELEX technology.
Until the end of the project we are going to continue characterizing the mechanisms whereby mechanotransduction in CAFs influences therapeutic responses. Briefly, we will investigate the molecular and biological processes implicated, which will inform of strategies to diminish the aberrant phenotypes. These will be extensively validated using the in vitro and in vivo methodology developed through this project. In addition, we will assess the clinical relevance of identified factors for their potential to predict treatment responses in CRC patients. Finally, we will generate aptamer-based probes to selectively identify those particular sets of CAFs implicated in therapeutic resistance, which will be subsequently employed to develop CAF biomarkers and anti-CAF therapies.
Overall, our project should provide novel insights into the mechanisms whereby TME characteristics and CAFs influence tumorigenesis and response to therapy, which can then be harnessed through aptamer-based therapeutics developed by our group to monitor their status and serve as additional diagnostic tools to guide treatment options. In addition, it will inform the development of strategies to specifically target CAFs and improve patient outcomes to a wide range of therapies in CRC.