Lysophosphatidic acid-induced amphiregulin secretion by cancer-associated fibroblasts augments cancer cell invasion

Abstract

Cancer-associated fibroblasts (CAFs) are key structural components of the tumor microenvironment and are closely associated with tumor invasion and metastasis. Lysophosphatidic acid (LPA) is a biolipid produced extracellularly and involved in tumorigenesis and metastasis. LPA has recently been implicated in the education and transdifferentiation of normal fibroblasts (NFs) into CAFs. However, little is known about the effects of LPA on CAFs and their participation in cancer cell invasion. In the present study, we identified a critical role of LPA-induced amphiregulin (AREG) secreted from CAFs in cancer invasiveness. CAFs secrete higher amounts of AREG than NFs, and LPA induces AREG expression in CAFs to augment their invasiveness. Strikingly, knocking out the AREG gene in CAFs attenuates cancer invasiveness and metastasis. Mechanistically, LPA induces Yes-associated protein (YAP) activation and Zinc finger E-box binding homeobox 1 (Zeb1) expression through the LPAR1 and LPAR3/Gi/Rho signaling axes, leading to AREG expression. Furthermore, we provide evidence that metformin, a biguanide derivative, significantly inhibits LPA-induced AREG expression in CAFs to attenuate cancer cell invasiveness. Collectively, the present data show that LPA induces AREG expression through YAP and Zeb1 in CAFs to promote cancer cell invasiveness, with the process being inhibited by metformin, providing potential biomarkers and therapeutic avenues to interdict cancer cell invasion.