Secretion of IL1 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, in part through their contractile properties. Swelling of tumor-draining lymph nodes 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 premetastatic lymph node 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–RHO–kinase (ROCK) pathway and the mechano-responsive transcriptional coactivator Yes1 associated transcriptional regulator (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 lymph node in premetastatic mouse models. Finally, IL1 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 premetastatic lymph node niche. Targeting this remote communication could be an effective strategy to prevent metastatic spread of the disease. Significance: Communication between dedifferentiated melanoma cells and lymph node fibroblasts reprograms the biomechanical properties of the premetastatic lymph node niche to promote tumor invasion. See related commentary by Lund, p. 1692

Revealing the oncogenic role of elevated GNL3L expression in esophageal squamous cell carcinoma: insights into the STAT3 pathway

“…Interestingly, our protein-protein interaction (PPI) analysis did not confirm a direct interaction between GNL3L and STAT3. Subsequent literature review uncovered evidence indicating that JAK1 , IFNAR1 , IFNAR2 , and EML4 can activate the STAT3 signaling pathway, contributing to tumor progression ( 23 - 25 ). Correspondingly, our bioinformatics analysis substantiated a positive correlation between GNL3L expression and that of JAK1 , IFNAR1 , IFNAR2 , and EML4 .…”

The transcription factor SpiB regulates Fibroblastic Reticular Cell network and CD8+T cell responses in lymph nodes

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Protective fibroblastic niches in secondary lymphoid organs

“…Lactic acid, a metabolite released by cancer cells and found to be enriched in tumor-draining LNs of preclinical melanoma and breast cancer models, was identified to modulate FRC metabolism and mitochondrial function, leading to FRC activation as marked by upregulation of PDPN and Thy1 and downregulation of IL-7, without affecting survival and proliferation of FRCs ( Riedel et al, 2022 ). Furthermore, soluble factors released by dedifferentiated melanomas are found to promote FRC elongation, proliferation, and upregulation of the activation markers PDPN, tenascin C, fibronectin, and IL6 in vitro ( Rovera et al, 2022 ). Among the factors secreted by dedifferentiated melanoma cells, IL1α and IL1β cytokines inhibit the contractility of primary human LN fibroblasts and thereby enhance cancer cell invasiveness in vitro.…”

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