Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating co-morbidity of PDAC with unknown etiology. Previously our lab demonstrated that systemic increases in Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) is 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 in the KCKO and Ptf1a tm1(cre)Cvw/WT ;Kras tm4Tyj/WT ; Trp53tm5Tyj/tm 5Tyj (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 5- and 6-fold decrease in myocellular lipid accumulation vs 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 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 non-canonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway.
Sechrist et al. (Mon,) studied this question.