Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of AGTR1+ CAFs in intrahepatic cholangiocarcinoma.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA. Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA-seq and ATAC-seq were used for mechanistic investigations. Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer-associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of AGTR1+ CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co-cultured CAFs and iCCA cells. Still, they did not have a significant effect on AGTR1- CAFs. Moreover, ARBs decreased the secretion of AGTR1+ CAF-derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells. ARBs exhibit anti-fibrotic function by inhibiting the viability of AGTR1+ CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.