ACLP promotes activation of cancer-associated fibroblasts and tumor metastasis via ACLP-PPARγ-ACLP feedback loop in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Its fibrotic tumor microenvironment (TME) plays a crucial role in promoting tumor invasion and metastasis, which eventually leads to a dismal 5-year survival rate in PDAC patients. Aortic carboxypeptidase-like protein (ACLP) promotes tissue fibrosis in benign diseases. However, its role in cancer-associated fibrosis remains unelucidated. Here, we show that ACLP was mainly expressed in cancer-associated fibroblasts (CAFs) but not in cancer cells and highly expressed in PDAC tissues. High ACLP expression was correlated with poor overall survival. Moreover, ACLP expression in PDAC patients with liver metastases was higher than that in PDAC patients without liver metastases. By detecting activation marker expression and CAF contractility and motility, we found that ACLP promoted CAF activation in PDAC, leading to TME fibrosis. Furthermore, ACLP-activated CAFs could promote cancer cell invasion in vitro and tumor metastasis in vivo. Mechanistically, ACLP promotes the expressions of MMP1 and MMP3 in CAFs, thus promoting PDAC invasion and metastasis. Intriguingly, we identified an ACLP-PPARγ-ACLP feedback loop in PDAC CAFs. Abatement of this feedback loop might be a promising approach in CAF-targeting PDAC treatment.