LAUSR

JAK-STAT signalling is a cornerstone to cancer progression, either as a tumour intrinsic driver of cancer growth/metastasis, or as a modulator of immune surveillance. This Special Issue highlights new research findings underlying the contribution of JAK-STAT signalling to multiple cancer types, and provides up to date reviews in this critical area from leaders in this field. Constitutive activation of JAK-STAT signalling can arise through a number of different mechanisms, including the elevated expression of cytokines. The hallmark example is upregulated interleukin (IL)-6, which signals through either a ‘classic’ mechanism that is restricted by cell-type specific expression of IL-6 receptor α (IL-6Rα), which engages with the ubiquitously expressed β-subunit receptor, GP130. The result is increased Janus kinase (JAK) mediated activation of an oncogenic transcription factor, signal transducer and activator of transcription (STAT)3 [1]. Alternatively, IL-6 ‘trans-signalling’, mediated by IL-6 engagement with a soluble IL-6Rα, can lead to activation of JAK-STAT signalling in any cell [2]. It is now understood that a disintegrin and metalloproteinase 17 (ADAM17) is responsible for the protease-driven shedding of IL-6R [2], revealing a previously unappreciated opportunity to therapeutically modulate IL-6 mediated signalling, with extensive reviews focused on the relevance of IL-6/IL-6R/GP130 to hepatocellular carcinoma and lung cancer provided in this issue [1,2]. Activating mutations in GP130 have been reported that result in ligand independent activation of STAT3 in liver cancers [1]. Activating mutations have also been reported in other cytokine receptors upstream of JAK-STAT, including IL7RA, with a review in this issue providing a new framework for classification of these mutations, based on their structural consequences and biological activity, with oncogenic mutations in acute lymphoblastic leukaemia (ALL) exclusively found in the extracellular and transmembrane regions [3]. While activating mutations in cytokine receptors are not common, or at least not heavily investigated, activating mutations are commonly found in JAK1 and JAK2, which is best highlighted by the literature in myeloproliferative neoplasms and leukaemia. In this issue, a novel JAK1 Y1034C somatic activating mutation was identified from whole genome sequencing of spontaneously occurring rat natural killer large granular lymphocyte leukaemia [4]. Many oncogenic mutations are located in the JAK pseudokinase domain, which is thought to play an essential role in keeping the kinase inactive in absence of ligand binding to a cytokine receptor. This issue includes an enhanced mechanistic understanding of the JAK1 pseudokinase domain in cytokine signalling [5]. Surprisingly, characterisation of the enzyme activity of purified recombinant JAK1 proteins demonstrated that the oncogenic V658F mutation, in the pseudokinase domain, showed no enhancement of intrinsic kinase activity compared to wild-type JAK1 [6]. This study suggests that the structure and interactions of JAK1 in the cellular context are critical for preventing JAK from being activated in the absence of cytokine. STAT3 is constitutively activated in numerous cancers. This issue includes multiple new studies investigating the role of STAT3 signalling in several solid malignancies (bladder, breast, medulloblastoma, colon, and cervical cancers), as well as blood cancers (including leukaemia).