Secretion of interleukin-1 by dedifferentiated melanoma cells inhibits JAK1-STAT3-driven actomyosin contractility of lymph node fibroblastic reticular cells

ABSTRACT: Fibroblastic reticular cells (FRC) are immunologically specialized myofibroblasts that control the elasticity of the lymph node (LN), in part through their contractile properties. Swelling of tumor-draining LN is a hallmark of lymphophilic cancers such as cutaneous melanoma. Melanoma displays high intratumoral heterogeneity with the coexistence of melanoma cells with variable differentiation phenotypes, from melanocytic to dedifferentiated states. Factors secreted by melanoma cells promote pre-metastatic LN reprograming and tumor spreading. Elucidating the impact of the melanoma secretome on FRC could help identify approaches to prevent metastasis. Here we show that melanocytic and dedifferentiated melanoma cells differentially impact the FRC contractile phenotype. Factors secreted by dedifferentiated cells, but not by melanocytic cells, strongly inhibited actomyosin-dependent contractile forces of FRC by decreasing the activity of the RHOA-ROCK pathway and the mechano-responsive transcriptional co-activator YAP. Transcriptional profiling and biochemical analyses indicated that actomyosin cytoskeleton relaxation in FRC is driven by inhibition of the JAK1-STAT3 pathway. This FRC relaxation was associated with increased FRC proliferation and activation and with elevated tumor invasion in vitro. The secretome of dedifferentiated melanoma cells also modulated the biomechanical properties of distant LN in pre-metastatic mouse models. Lastly, interleukin-1 produced by dedifferentiated cells was involved in the inhibition of FRC contractility. These data highlight the role of the JAK1-STAT3 and YAP pathways in spontaneous contractility of resting FRC. They also suggest that dedifferentiated melanoma cells specifically target FRC biomechanical properties to favor tumor spreading in the pre-metastatic LN niche. Targeting this remote communication could be an effective strategy to prevent metastatic spread of the disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157355 | GEO | 2022/02/16

REPOSITORIES: GEO