Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia

/NARRATIVE Cancer cachexia (CCX), wasting of muscle and/or adipose, is associated with 20-30% of all cancer related deaths.1 Our clinical studies have shown that the presence of CCX is associated with a 50% decrease in median survival (14 months vs 28 months, p<0.001) independent of tumor-directed therapies.2-3 There are no FDAapproved CCX regimens, with a majority of trials focused on limiting sarcopenia. Using multiple established murine CCX mouse models, we consistently observed significant adipose tissue loss compared to muscle atrophy. Furthermore, blocking adipocyte lipolysis using global lipase null mice limited both adipose wasting and sarcopenia in murine models of CCX. Understanding upstream mechanisms cancers use to provoke adipose lipolysis and wasting could offer novel therapeutic targets to reverse CCX syndrome. The complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately regulate CCX wasting by altering the relative signals of adipocyte triglyceride lipolysis and synthesis. To understand the convergence of these interactions, we developed an in vitro CCX adipocyte assay to screen secreted factors from CCX lines that increase adipose inflammation and wasting by inducing adipocyte lipolysis and identified the cytokine leukemia inhibitory factor (LIF).5 Through the JAK-dependent inflammatory reprogramming of adipose tissue in mice, recombinant LIF caused a decrease in adipose mass by >50%, lean mass, and body weight by >10%, recapitulating CCX. LIF also altered the adipose expression and systemic levels of other cyto/adipokines to amplify this inflammation and alter food intake. Use of JAK inhibitors in murine CCX models led to decreased adipose inflammation (decreased STAT3 phosphorylation), adipocyte lipolysis, and adipose/muscle wasting, all increasing survival. To understand the contributions of adipose intracellular signaling in the regulation of CCX adipose inflammation, we selectively silenced the LIF receptor (LIFR) or STAT3 in adipocytes. Both mouse models doubled their adipose mass compared to littermate controls during development highlighting an inverse CCX phenotype. When allotransplanted with CCX tumors, both models still demonstrated adipose inflammation with persistent STAT3 phosphorylation, resulting in a partial suppression of CCX and defining the non-adipocyte cellular contributions of adipose to CCX wasting. FACS analysis verified longitudinal enrichment of immune cells during CCX progression, offering additional tumor/cytokine targets supporting CCX adipose inflammation and wasting. We hypothesize that CCX adipose inflammation occurs via a JAK-dependent Tumor-Cytokine-Adipose Axis that reprograms adipose through JAK/STAT signaling of multiple cellular subtypes to increase adipocyte lipolysis and alter secretion of cyto/adipokines, resulting in wasting. SA1-2 will dissect the multiple cellular/molecular signaling components of this axis facilitating adipose inflammation in support of this CCX wasting. SA3 will validate associations between JAK/STAT signaling events in human adipose to CCX induction in patients.