S4, ACD), with changes in gene expression similar across both tumor conditions, while iPathway highlighted cytokine signaling, metabolism, and JAK-STAT signaling (Fig. over 80% of patients with PDAC and leads to increased morbidity and mortality (Hendifar et al., 2018; Sun et al., 2015; von Haehling et al., 2016). Both cancer and cachexia are associated with systemic inflammation affecting multiple organ systems (Argils et al., 2019; Onesti and Guttridge, 2014). While various cytokines, chemokines, and growth factors are changed in PDAC, IL-6 specifically has been positively correlated with PDAC presence (Holmer et al., 2014), disease progression (Ramsey et al., 2019), mortality (Babic et al., 2018; Suh et al., 2013), and cachexia (Okada et al., 1998; Ebrahimi et al., 2004; Martignoni et al., 2005). Although circulating IL-6 levels are not always detectable in early PDAC nor always correlated with cachexia MDM2 Inhibitor severity (Ramsey et al., 2019; Talbert et al., 2018), higher tumor staining for IL-6 is usually associated with PDAC cachexia (Martignoni et al., 2005) and induction of monocyte IL-6 is usually predictive of survival in PDAC (Moses et al., MDM2 Inhibitor 2009), suggesting that this serum levels of this short-lived cytokine might not be an appropriate measure of tissue activity. Functional data also support a role for MDM2 Inhibitor IL-6 in PDAC tumor development (Lesina et al., 2011), progression (Zhang et al., 2013), metastasis (Razidlo et al., 2018), antitumor immunity (Flint et al., 2016), and response to chemotherapy (Long et al., 2017). IL-6 levels are high in PDAC models with weight loss (Flint et al., 2016), and IL-6 is usually functionally linked to cachexia in murine C26 colon adenocarcinoma and other models of cancer cachexia (Baltgalvis et al., 2008; Bonetto et al., 2012; Bonetto et al., 2011; Narsale and Carson, 2014). Moreover, IL-6 is sufficient to induce cachexia in mice (Baltgalvis et al., 2009; Chen et al., 2016; Tsujinaka et al., 1996) as well as lipolysis and atrophy in cultured adipocytes (Trujillo et al., 2004) and myotubes (Bonetto et al., 2012), respectively. IL-6 can be both detrimental and beneficial. While chronically increased IL-6 is usually associated with insulin resistance, inflammation, adipose tissue lipolysis, and muscle wasting in diseases from cancer and obesity to sepsis and burn injury (Kraakman et al., 2015; Pedroso et al., 2012; van Hall, 2012), acute expression of IL-6 promotes liver regeneration after injury (Jin et al., 2006; Koniaris et al., 2003) and is required for muscle regeneration, exercise-induced hypertrophy, and recovery from disuse atrophy (Begue et al., 2013; McKay et al., 2009; Washington et al., 2011). IL-6 initiates signal transduction by first binding to either the membrane-bound form of the IL-6 receptor (IL6R), also known as glycoprotein 80 (GP80), or its soluble form (sIL6R; Schaper and Rose-John, 2015). Proteolytic shedding of a 55-kD fragment in tissues expressing membrane IL6R results in circulating sIL6R (Schaper and Rose-John, 2015), an activity mediated in part through intracellular accumulation of phorbol esters and activation of protein kinase C (PKC; Mllberg et al., 1992). Both complexes of IL-6 with membrane or sIL6R bind the ubiquitously expressed membrane coreceptor IL-6 signal SPTAN1 transducer, also known as glycoprotein 130 (GP130). The activity elicited by IL-6 and membrane IL6R is considered classical or cis signaling, while activity instigated by IL-6 with sIL6R is known as trans-signaling. Formation of either complex leads to trans-phosphorylation and activation of JAKs, which phosphorylate the transcription factor STAT3, promoting STAT3.