scholarly journals Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node

2021 ◽  
Author(s):  
Christopher Rovera ◽  
Ilona Berestjuk ◽  
Margaux Lecacheur ◽  
Serena Diazzi ◽  
Aude Mallavialle ◽  
...  

AbstractFibroblastic reticular cells (FRC) are immunologically specialized fibroblasts controlling the size and microarchitecture of the lymph node (LN), partly through their contractile properties. Swelling is a hallmark of tumor-draining LN in lymphophilic cancers such as cutaneous melanoma, a very aggressive and heterogeneous tumor with high risk of early metastasis. Melanoma cells can dynamically switch between melanocytic proliferative and dedifferentiated mesenchymal-like invasive phenotypes, which are characterized by distinct transcriptional signatures. Melanoma secreted cues, such as extracellular vesicles, growth factors or proinflammatory cytokines, promote LN stroma remodeling and metastatic spreading. But how FRC integrate these pro-metastatic signals and modulate their contractile functions remains poorly characterized. Here, we show that factors secreted by dedifferentiated melanoma cells, but not by melanocytic cells, strongly inhibit FRC actomyosin-dependent contractile forces by decreasing the activity of the RHOA-ROCK pathway and the mechano-responsive transcriptional co-activator YAP, leading to a decrease in F-actin stress fibers and cell elongation. Transcriptional profiling and biochemical analyses indicate that FRC actomyosin cytoskeleton relaxation is driven by inhibition of JAK1 and its downstream transcription factor STAT3, and is associated with increased FRC proliferation and activation. Interestingly, dedifferentiated melanoma cells reduce FRC contractility in vitro independently of extracellular vesicle secretion. These data show that FRC are specifically modulated by proteins secreted by invasive dedifferentiated melanoma cells and suggest that melanoma-derived cues could modulate the biomechanical properties of distant LN before metastatic invasion. They also highlight that JAK1-STAT3 and YAP signaling pathways contribute to the maintenance of the spontaneous contractility of resting human FRC.

2019 ◽  
Vol 95 (2) ◽  
pp. 310-320 ◽  
Author(s):  
Vivek Kasinath ◽  
Osman A. Yilmam ◽  
Mayuko Uehara ◽  
Liwei Jiang ◽  
Farideh Ordikhani ◽  
...  

2021 ◽  
Author(s):  
Joshua D'Rozario ◽  
Konstantin Knoblich ◽  
Mechthild Luetge ◽  
Christian Perez Shibayama ◽  
Hung-Wei Cheng ◽  
...  

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis. The T cell paracortical zone is a major site of macrophage efferocytosis of apoptotic cells, but key factors controlling this niche are undefined. Here we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Macrophages co-localised with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that most reticular cells expressed master macrophage regulator CSF1. Functional assays showed that CSF1R signalling was sufficient to support macrophage development. In the presence of LPS, FRCs underwent a mechanistic switch and maintained support through CSF1R-independent mechanisms. These effects were conserved between mouse and human systems. Rapid loss of macrophages and monocytes from LNs was observed upon genetic ablation of FRCs. These data reveal a critically important role for FRCs in the creation of the parenchymal macrophage niche within LNs.


2020 ◽  
Vol 13 (5) ◽  
pp. 419-434
Author(s):  
Freddy Gonzalez Badillo ◽  
Flavia Zisi Tegou ◽  
Riccardo Masina ◽  
Shane Wright ◽  
Mackenzie Scully ◽  
...  

2015 ◽  
Vol 99 (8) ◽  
pp. 1561-1567 ◽  
Author(s):  
Yumi Nakayama ◽  
C. Colin Brinkman ◽  
Jonathan S. Bromberg

Author(s):  
Lushen Li ◽  
Jing Wu ◽  
Reza Abdi ◽  
Christopher M. Jewell ◽  
Jonathan S. Bromberg

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