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 [Ptf1a^tm1-cre/+;Kras^tm4Tyj;Muc1^-/- (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 Ptf1a^{tm1(cre)Cvw/WT};Kras^tm4Tyj/WT;Trp53^{tm5Tyj/tm5Tyj} (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with IGFBP-3^-/- 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 (fbxo32 and trim32), Autophagy (ULK1 and LC3bII), and transforming growth factor-β receptor (TGF-βR) signaling (tgfβr1 and FOXO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with IGFBP-3^-/- 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.NEW & NOTEWORTHY 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.

IGFBP-3; PDAC; cancer cachexia; skeletal muscle.