Tamoxifen calms down the distressed PDAC stroma

Abstract

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 1, 2 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. The two studies thus open up new opportunities to explore tamoxifen as potential anti‐stromal therapy in PDAC.

Figure 1. PDAC desmoplasia is suppressed by tamoxifen modulation of the tumor stroma

(A) PDAC is characterized by a pronounced fibrotic stroma termed desmoplasia. The altered stroma promotes infiltration of macrophages and invasion of cancer cells. Tamoxifen treatment inhibits the function of reactive stellate cells, infiltrating macrophages, including M2 macrophages, and the cancer cells themselves in the tumors. This leads to reduced cancer cell invasion and proliferation as well as increased apoptosis. Tissues become more vascularized, potentially improving drug delivery to tumors, and hypoxic responses are reduced. (B) Pancreatic stellate cells are the key cell type involved in the fibrotic response and regulate tumor biomechanical properties via contraction and ECM modulation. Tamoxifen acts as agonist of GPER in pancreatic stellate cells, repressing genes that drive contraction and ECM remodeling in PDAC.