ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC.

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…Using clinical specimen and experimental mouse models, Laklai et al identified a distinct, highly stiff, matricellular-stromal phenotype that was specifically associated with reduced epithelial transforming growth factor (TGF)-β signalling, elevated β-integrin mechano-signalling and Stat3 activation resulting in therapeutic resistance and significantly shortened survival in mice and humans 37. In line with these findings, ATRA, an active metabolite of vitamin A, was reported to reprogram mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta-dependent downregulation of actomyosin contractility 38. Furthermore, Rho kinase (ROCK) signalling, Yes-associated protein 1 and Janus kinase 2 and signal transducer and activator of transcription 3 signalling pathways have been associated with tissue tension and tumour cell contractility 39–41…”

Targeting the tumour stroma to improve cancer therapy

“…Agents targeting LOX activity could decrease collagen crosslinking, thereby reducing the density of the tumour stroma and increase the effectiveness of anticancer therapies 279–282 . The vitamin D receptor ligand calcipotriol 283 and all-trans retinoic acid (ATRA) 284 are other agents that reduced fibrosis in experiments with PDAC models.…”

Pancreatic cancer: a mechanobiology approach

“…Similarly, all trans-retinoic acid (ATRA), the physiological active metabolite of vitamin A, restores mechanical quiescence in PSCs via activation of the retinoic acid receptor beta (RAR-β) and down regulation of actomyosin contractility, which suppresses the ability of PSCs to apply forces and mechanosense matrix rigidity. Mechanically quiescent PSCs are unable to remodel and stiffen the matrix, and this creates a microenvironment that is not favourable for pancreatic cancer cell invasion (figure 2) [35]. Notably, PSCs were removed from remodelled collagen/matrigel matrices before cancer cell invasion in these in vitro experiments; thus, the reduced ability of cancer cells to invade was related to the mechanical and/or topological changes in the ECM.…”

“…Bottom, bright field images of PSC and its corresponding force map. Panel reproduced from [35]. CC BY 4.0.…”