Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

Mechanotaxis and mechanoresistance in cancer

Pancreatic cancer is a devastating disease with a very poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterised by excessive deposition of extracellular matrix proteins which ultimately leads to a stroma with increased stiffness. High stiffness gives rise to perpetuation of the disease through activation of stromal components that further exacerbate disease aetiology. This process is termed as mechanosensing where the cell is able to mechanically sense the external environment resulting in mechanotransduction, which is the conversion of these mechanical cues into biochemical ones leading to intracellular changes that allow cells to adapt to their microenvironment. Studies presented here, focused on pancreatic stellate cells (PSCs), fundamental stromal cells that play a critical role in the maintenance of the pancreatic stroma and upholding of tissue homeostasis. In diseased states, PSCs can negatively affect tissue regulation and aid in a positive feedback mechanism to intensify disease pathology. Through rigidity guided migration i.e. durotaxis, cells mechanically sense their substrate and generate forces to migrate to more rigid regions. Here, the fabrication of substrates that mimic the stiffness of healthy and fibrotic tissue which would be seen in vivo in pancreatic cancer, the effect that these substrates have on focal adhesion dynamics and subsequent cell migration is demonstrated. Another major hurdle faced in pancreatic cancer is resistance acquired in response to drug therapy. This resistance can occur in the form of a physical barrier like the fibrotic stroma that hampers effective drug delivery, or drug resistance in response to upregulation of various signalling pathways leading to drug efflux and increased drug metabolism. Gemcitabine is currently the standard chemotherapeutic used to treat pancreatic cancer but many patients acquire resistance to therapy within the first few weeks of treatment. Here, it is shown that using combination therapy gemcitabine and G protein coupled estrogen receptor (GPER) agonist G1, increased cell apoptosis and decreased cell proliferation demonstrating that combination therapy could offer a possible therapeutic route in targeting this disease.Open Acces

Chemoresistance and the Self-Maintaining Tumor Microenvironment

The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the ECM can promote chemoresistance in cancer cells through a variety of signaling pathways, inducing changes in gene expression and protein activity that allow resistance. Furthermore, the ECM is maintained as an environment that facilitates chemoresistance, since its constitution modulates the phenotype of cancer-associated cells, which themselves affect the microenvironment. In this review, we discuss how the properties of the tumor microenvironment promote chemoresistance in cancer cells, and the interplay between these external stimuli. We focus on both the response of cancer cells to the external environment, as well as the maintenance of the external environment, and how a chemoresistant phenotype emerges from the complex signaling network present

Chemoresistance and the self-maintaining tumor microenvironment

The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the ECM can promote chemoresistance in cancer cells through a variety of signaling pathways, inducing changes in gene expression and protein activity that allow resistance. Furthermore, the ECM is maintained as an environment that facilitates chemoresistance, since its constitution modulates the phenotype of cancer-associated cells, which themselves affect the microenvironment. In this review, we discuss how the properties of the tumor microenvironment promote chemoresistance in cancer cells, and the interplay between these external stimuli. We focus on both the response of cancer cells to the external environment, as well as the maintenance of the external environment, and how a chemoresistant phenotype emerges from the complex signaling network present