GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment

Abstract

The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein‐coupled estrogen receptor (GPER), is widely used to treat estrogen‐positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER‐mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto‐myosin‐dependent manner via RhoA‐mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor‐associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well‐established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.

Tamoxifen mechanically reprograms the tumor microenvironment via HIF ‐1A and reduces cancer cell survival

“…Therefore, the effect of tamoxifen on decreasing collagen synthesis by PSCs does not only alleviate fibrosis, but also might hamper cancer cells survival under nutrient limited conditions. In an accompanying report in this issue [48], we show that tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells and their ability to remodel the tumor microenvironment in PDAC via a mechanotransduction mechanism that involves GPER and YAP. Our observations that tamoxifen inhibits fibronectin, collagen, and HIF-1A expression suggest other links between hypoxia and mechanotransduction.…”

Clinical candidate and genistein analogue AXP107‐11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein‐coupled estrogen receptor signaling

“…Our in vivo experiments did not fully capture this clinical presentation, and it is not clear if the proposed GPER1 treatment would overcome this obstacle. However, a recent study which used tamoxifen, which also acts as a GPER1 agonist, in a mouse model of pancreatic cancer, found that this could modify the microenvironment and reduce desmoplasia, inflammation, and immune suppression in PDAC …”

Tamoxifen calms down the distressed PDAC stroma

“…In line with these changes, alpha smooth muscle actin (α‐SMA) expression is reduced in tamoxifen‐treated KPC mice, indicating impaired activation of PSCs . Using magnetic bead displacement, gel contraction, and matrix remodeling assays, the authors find that tamoxifen indeed inhibits the myofibroblastic differentiation of PSCs, and that this is GPER dependent . Tamoxifen‐treated PSCs lose their ability of actomyosin contraction by reduced activation of the mechanotransducers RhoA and myosin light chain 2 (MLC‐2).…”

“…In this issue of EMBO Reports, Cortes et al [1,2] present two complementing studies that unveil tamoxifen-GPER axis as an essential regulator of the PDAC microenvironment (summarized in Fig 1). They show that tamoxifen has pleiotropic effects, targeting PSCs, macrophages, and cancer cells within tumors of KPC mice (Kras G12D/+ ; p53 R172H/+ ; Pdx-1-Cre), an established model of PDAC.…”

“… Pancreatic ductal adenocarcinoma ( PDAC ) is one of the deadliest human cancers and is associated with extensive desmoplastic changes in the tumor microenvironment. In this issue of EMBO Reports , two studies by Cortes et al identify the G‐protein‐coupled estrogen receptor ( GPER ) as an important regulator of the PDAC ‐associated stroma, modulating tissue stiffness, hypoxic responses, and desmoplasia. Intriguingly, the authors find that tamoxifen, which is widely used for its antagonizing effect on nuclear estrogen receptor ( ER )‐positive breast cancers, acts as GPER agonist to normalize the PDAC microenvironment.…”