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Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis. [ABSTRACT FROM AUTHOR]

Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130 F/F spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis. sIL-11R protein was detectable in gastric tissue from GC patients, and sIL-11R levels were elevated in tumours of gp130 F/F mice compared to matched non-tumours. Among candidate proteases associated with the generation of sIL-11R, ADAM10 and the related metalloprotease ADAM17 were significantly upregulated in tumours of both gp130 F/F mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130 F/F mice upon the transgenic over-expression of the trans-signalling antagonist, sgp130Fc, failed to suppress gastric inflammation and associated tumour growth, and also had no effect on reducing hyper-activated STAT3 levels. Furthermore, a non-essential role for ADAM17 in IL-11-driven gastric tumourigenesis was supported by the observation that the tumour burden was unaffected in gp130 F/F : Adam17 ex/ex mice in which ADAM17 expression levels have been substantially reduced. Collectively, these findings suggest that classic signalling rather than trans-signalling is the mode by which IL-11 promotes gastric tumourigenesis. [ABSTRACT FROM AUTHOR]

Deregulated activation of the latent transcription factor STAT3 has been implicated in the pathogenesis of myeloproliferative and lymphoproliferative hematologic disorders. The uncontrolled activation of STAT3 has traditionally been assigned to its elevated phosphorylation at tyrosine 705 (pY 705) and associated nuclear transcriptional activity. By contrast, a transcriptional role for serine 727 phosphorylation (pS 727) of STAT3 has recently emerged, suggesting that pS 727 may account for the pathological activity of STAT3 in certain disease settings. Here, by coupling pS 727 -STAT3-deficient Stat3 SA/SA mice with a STAT3-driven mouse model (gp130 F/F) for myeloproliferative and lymphoproliferative pathologies, we reveal a key role for pS 727 -STAT3 in promoting multiple hematologic pathologies. The genetic blockade of pS 727 -STAT3 in gp130 F/F: Stat3 SA/SA mice ameliorated the neutrophilia, thrombocytosis, splenomegaly and lymphadenopathy that are features of gp130 F/F mice. The protection against thrombocytosis in gp130 F/F: Stat3 SA/SA mice coincided with normalized megakaryopoiesis in both bone marrow and spleen compartments. Interestingly, pS 727 -STAT3-mediated abnormal lymphopoiesis in gp130 F/F mice was more pronounced in lymph nodes compared to thymus, and was characterized by elevated numbers of B cells at the expense of T cells. Furthermore, pS 727 -STAT3 dependency for these hematologic pathologies coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic genes. Collectively, these findings suggest that pS 727 plays a critical pathological role in modulating the transcriptional activity of STAT3 in hematologic disorders. [ABSTRACT FROM AUTHOR]