LAUSR

BACKGROUND & AIMS Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. ACSS2 is an acetyl-coA synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the non-selective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer. METHODS Clinical significance of ACSS2 was analyzed using human pancreatic cancer patient samples. ACSS2 knockout cells were established utilizing CRISPR-Cas9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. Macropinocytotic index was evaluated by dextran uptake assay. ChIP assay was performed to validate transcriptional activation. ACSS2 mediated tumor progression and muscle wasting were examined in orthotopic xenograft models. RESULTS Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2D and 3D models. Macropinocytosis associated genes are upregulated in tumor tissues and are correlated to worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified ZIP4 as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2 induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4 mediated transcriptional activation. ZIP4 induces macropinocytosis through CREB activated SDC1 and DNM2. Meanwhile, ZIP4 drives muscle wasting and cachexia via GSK3β mediated secretion of TRAIL. ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models. CONCLUSIONS ACSS2-mediated metabolic reprogramming activates ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.