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ATRA has also been shown to promote cell compliance in acute promyelocytic leukemia via cytoskeletal remodelling.Therefore, we hypothesized that the ability of ATRA to promote cell compliance and to reduce ECM remodelling could interfere with the priming and activation TGF-β by PSCs.To understand whether a similar alternative splicing mechanism occurs in PSCs, we examined the expression of fibronectin-EDA, which is the major isoform expressed in breast cancer, and fibronectin-EDB, which has been implicated in pancreatic cancer microenvironment but of an unknown cellular origin Fibronectin alternative splicing in PSCs under ATRA treatment and effect of fibronectin knock-down and excess fibronectin incubation on fibronectin/LTBP-1 lining (a) Q-PCR targeting fibronectin-EDA or fibronectin-EDB m RNA showed a significant decrease in fibronectin-EDA and fibronectin-EDB levels in ATRA treatment group in comparison to control PSC cells.

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.LTBP-1 and fibronectin co-immunostaining showed that in ECM that is remodelled by control PSCs, LTBP-1 can be organised onto fibronectin-positive fibrils (Fig. In contrast, LTBP-1 remains in patches when deposited by HEK-293 alone (Fig.S1b) as further evidenced by the near zero Pearson correlation coefficient of LTBP-1/fibronectin co-localisation (not shown).

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