Ablation of tumor-derived IGFBP-3 attenuates cancer-associated skeletal muscle wasting in murine pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating comorbidity of PDAC with unknown etiology. Previously, our lab demonstrated that systemic increases in insulin-like growth factor-binding protein-3 (IGFBP-3) are associated with SMW and pathologic myocellular lipid accumulation in an orthotopic murine model of PDAC [<i>Ptf1a</i>^tm1-cre/+;<i>Kras</i>^tm4Tyj;<i>Muc1</i>^-/- (KCKO)]. Here we show that PDAC tumor cells secrete high levels of IGFBP-3 and that genetic ablation of IGFBP-3 (IGFBP-3^-/-) in the KCKO and <i>Ptf1a</i>^{tm1(cre)Cvw/WT};<i>Kras</i>^tm4Tyj/WT;<i>Trp53</i>^{tm5Tyj/tm5Tyj} (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with <i>IGFBP-3</i>^-/- tumors lost 10- and 3-fold less appendicular lean mass, and experienced a five- and sixfold decrease in myocellular lipid accumulation versus mice with parental KCKO and KP2 tumors, respectively, at failure to thrive endpoints. Gene expression studies demonstrated increases in the ubiquitin-proteasome pathway (<i>fbxo32</i> and <i>trim32</i>), autophagy (ULK1 and LC3bII), and transforming growth factor-β receptor (TGF-βR) signaling (<i>tgfβr1</i> and FoxO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with <i>IGFBP-3</i>^-/- tumors. In vitro studies confirmed a role for IGFBP-3 in stimulating TGF-β receptors and regulating SMAD3 nuclear localization. Moreover, IGFBP-3 deletion in tumor cells and small molecule inhibition of TGF-βR1/2 attenuated myotube wasting. Collectively, these results suggest that PDAC-derived IGFBP-3 promotes SMW via noncanonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway.<b>NEW & NOTEWORTHY</b> The mechanism underlying PDAC-associated SMW is not well understood but has been connected to increases in systemic IGFBP-3 to supraphysiologic levels, resulting in dysregulated protein synthesis and catabolism signaling. Here, we show that genetic deletion of IGFBP-3 in orthotopic PDAC tumors significantly improves survival and muscle phenotypes in mice. Molecular studies suggest the role for noncanonical IGFBP-3 signaling through TGF-β receptors. Thus, IGFBP-3 may be a therapeutic target in the treatment of PDAC-related SMW.