ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells

Abstract

The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.

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

“…For instance, fibronectin extra domain A (EDA) isoform is expressed in liver and breast cancer , while fibronectin extra domain B (EDB) has been implicated in the PDAC microenvironment . Both isoforms, EDA and EDB, are secreted by PSCs .…”

“…For instance, fibronectin extra domain A (EDA) isoform is expressed in liver and breast cancer [33], while fibronectin extra domain B (EDB) has been implicated in the PDAC microenvironment [34]. Both isoforms, EDA and EDB, are secreted by PSCs [35]. We observed a significant decrease in the levels of gene expression of fibronectin (FN) and both splicing variants (FN-EDA and FN-EDB), and also a downregulation of FN at the protein level when PSCs were treated with tamoxifen versus untreated controls cells ( Fig 5A and B).…”

Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer

“…CAFs, the most abundant stromal cells, promote PDAC progression by producing high amounts of ECM and secreting various cytokines and growth factors, which in turn stimulate tumor growth, angiogenesis, invasion, and metastasis (5)(6)(7)31). hPSCs are regarded as the main precursors of CAFs in the pancreatic tumor stroma (16), and in response to TGF-b, they acquire a CAF-like myofibroblast phenotype, as we and others have previously shown (32)(33)(34). Recent studies have demonstrated that PSCs can differentiate into 2 different CAF subtypes: myofibroblastlike CAFs (driven by TGF-b) and inflammatory CAFs (driven by IL-1-induced JAK/signal transducer and activator of transcription pathway) (35,36).…”

Retinoic Acid Receptor‐β Is Downregulated in Hepatocellular Carcinoma and Cirrhosis and Its Expression Inhibits Myosin‐Driven Activation and Durotaxis in Hepatic Stellate Cells

“…HSCs are known to express all isoforms of the RAR family (α, β, and γ), each of which are differentially responsive to various retinoids . We treated HSCs with 1 µM ATRA for 10 days, a concentration and time comparable to those in previous studies on similar cells . The mRNA expression of RAR‐β was significantly increased in ATRA‐treated HSCs compared with control (Fig.…”