Abstract A120: Tumor-intrinsic MYC promotes a skeletal muscle-involving wasting phenotype in pancreatic ductal adenocarcinoma

Abstract

Cancer cachexia is defined by an ongoing loss of skeletal muscle mass, with or without loss of adipose tissue, and is particularly prevalent and severe in pancreatic ductal adenocarcinoma (PDAC). However, whether muscle and adipose wasting represent separable components of cachexia and are differentially shaped by tumor-intrinsic programs remains unclear. Here, we quantified a muscle wasting score (MWS) and a fat wasting score (FWS) from computed tomography images in 212 patients with resected PDAC, 178 of whom had matched tumor bulk RNA-sequencing data for pathway activity analyses associated with MWS and FWS. MWS and FWS were not significantly correlated (r = 0.01, p = 0.92, n = 212), indicating that muscle and adipose wasting can be uncoupled in PDAC cachexia. Increasing MWS was associated with enrichment of multiple inflammatory pathways, including TNFA/NF-κB signaling. Hallmark MYC Targets V1/V2 programs were also enriched with increasing MWS, whereas their associations with FWS were substantially weaker. Consistently, tumors from patients with muscle wasting, either alone or accompanied by adipose wasting, exhibited higher MYC activity than tumors from patients with adipose-only wasting. For functional validation, primary PDAC cells derived from spontaneous Ptf1aCreERT2; KrasG12D; c-Myc (KMC) tumors were transduced with control (shNC) or MYC-targeting (shMYC) shRNA and orthotopically transplanted into syngeneic C57BL/6 mice. Mice bearing shNC tumors developed progressive body-weight loss and had significantly shorter survival than mice bearing shMYC tumors. To minimize confounding by metastatic burden, mice were compared at a pre-metastatic stage with matched primary-tumor volumes. At this stage, shNC tumors induced approximately 20% loss of both gastrocnemius and tibialis anterior muscle mass, together with approximately 40% loss of epididymal white adipose tissue, whereas shMYC tumors caused approximately 18% adipose loss without measurable muscle wasting. Following metastatic progression, shNC tumors produced severe muscle wasting (∼35%) and near-complete adipose depletion (∼80%), compared with substantially milder losses in the shMYC group (∼8.5% muscle and ∼55% adipose loss). Thus, MYC suppression largely preserved skeletal muscle, whereas substantial adipose loss persisted. Consistent with these phenotypes, shNC tumors exhibited enhanced inflammatory and cachexia-related transcriptional programs, including increased expression of Il6, Il11, Cxcl1, Inhba, Angptl4, and Igfbp3. shNC tumors also developed more liver metastases and showed markedly increased phosphorylated STAT3 in both metastatic lesions and adjacent liver parenchyma, consistent with enhanced tumor–host inflammatory signaling. Collectively, these findings show that muscle and adipose wasting have distinct relationships with tumor-intrinsic MYC in PDAC cachexia. Tumor MYC promotes the emergence of a muscle-involving cachexia phenotype in the setting of ongoing adipose wasting, in association with cachexia-related secretory programs and enhanced STAT3 signaling.