Affecting more than 100,000 people worldwide, cystic fibrosis (CF) is caused by pathogenic variants of the CFTR gene. This debilitating disease affects a broad spectrum of organs but thanks to latest therapeutic advances with CFTR modulators, patient life expectancy now exceeds 40 years, hence transforming CF into a chronic disease of adulthood. Unfortunately, while ageing, patients with CF develop comorbidities including cardiovascular diseases, diabetes and cancer. The increased risk of developing cancer is likely multifactorial but could relate to the persistent pro-inflammatory state seen in patients with CF. Indeed, it is estimated that 25% of cancers worldwide are associated with infection and chronic inflammation. And chronic endothelial inflammation is implicated in pathologies leading to the development of cancer (e.g. obesity, diabetes, chronic inflammation of the intestine). However, the precise mechanism linking CFTR defect, the vascular compartment, and cancer onset is not fully understood.

In this study we combined in vitro, in vivo and scRNA-seq approaches to study the endothelium features after CFTR impairment. Particularly, we treated a normal model of endothelial cells (ECs) with a specific CFTR inhibitor to unravel, how CFTR loss impacts cancer cell invasion and immune cell trafficking. The effect of CFTR inhibition was also assessed in ovo using the chorioallantoic membrane (CAM) assay in chicken eggs combined with in situ imaging. Moreover, we investigated the vascular compartment of CF lung explant at the single cell level to have a glimpse into disease progression. Finally, we developed and characterize a unique mouse model of conditional and restricted CFTR invalidation in the vascular compartment (CFTR EC KO).

We showed that CFTR impairment directly dampen ECs and lung cancer cell migration. Interestingly, we present that CFTR-deficiency altered the endothelial barrier property, thereby increasing cancer cell migration and invasion and thus contributes to tumor progression. We have evidence that the endothelial-to-mesenchymal transition (EndMT) could be involved in this phenomenon. Moreover, our scRNA-seq data from CF lung explant revealed an endothelial state characterized by an exacerbated pro-inflammatory phenotype, which was absent in normal lung tissues. Hence, mirroring our recent data obtained in liver explants from CF patients. Finally, our first results in CFTR EC KO mouse model indicate vascular defects compared to control animals, which could have relevance for tumor onset.

The link between CFTR and cancer risk is clear, but the roles of CFTR during tumorigenesis and the involvement of ECs in this phenomenon are not yet well defined. In this study we have started to explore the mechanism by which endothelial CFTR-impairment could contribute to tumor progression via various mechanisms linked to endothelial plasticity and inflammation.