Nutrient Scavenging From Muscle Cells: A Survival Strategy of Pancreatic Cancer Cells Ends in Cachexia

See “Acetyl-coA synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer,” by Zhou Z, Ren Y, Yang J, et al, on page 1281. Pancreatic cancer cells undergo extensive metabolic rewiring to secure cell survival and tumor growth in a hypoxic and nutrient-deficient tumor microenvironment. To withstand these challenging growth conditions, pancreatic cancer cells rely on the recycling of intracellular components and increased metabolite uptake to produce energy and biomolecules for maintaining high anabolic activity.1Martinez-Reyes I. Chandel N.S. Cancer metabolism: looking forward.Nat Rev Cancer. 2021; 21: 669-680Crossref PubMed Scopus (182) Google Scholar Mutant KRAS, the main oncogenic driver of pancreatic cancer, not only supports tumor-promoting signaling pathways, but also contributes to increased nutrient uptake and metabolic conversion. In this way, mutant KRAS promotes the expression of the glucose transporter GLUT1, which triggers glucose uptake as well as glycolysis.2Yun J. Rago C. Cheong I. et al.Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.Science. 2009; 325: 1555-1559Crossref PubMed Scopus (692) Google Scholar In addition to controlling the gene expression of key metabolic transporters, activated RAS/MAPK signaling generates a dependence on nutrient scavenging pathways, such as autophagy, mitophagy and macropinocytosis to support the high nutrient demand of cancer cells.3Commisso C. Davidson S.M. Soydaner-Azeloglu R.G. et al.Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.Nature. 2013; 497: 633-637Crossref PubMed Scopus (1008) Google Scholar,4Piffoux M. Eriau E. Cassier P.A. Autophagy as a therapeutic target in pancreatic cancer.Br J Cancer. 2021; 124: 333-344Crossref PubMed Scopus (77) Google Scholar Autophagy recycles intracellular components and organelles, whereas mitophagy selectively degrades mitochondria.4Piffoux M. Eriau E. Cassier P.A. Autophagy as a therapeutic target in pancreatic cancer.Br J Cancer. 2021; 124: 333-344Crossref PubMed Scopus (77) Google Scholar The inhibition of the MAPK pathway increases sensitivity to inhibition of autophagy, showing synergistic antitumor effects.5Kinsey C.G. Camolotto S.A. Boespflug A.M. et al.Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers.Nat Med. 2019; 25: 620-627Crossref PubMed Scopus (326) Google Scholar,6Bryant K.L. Stalnecker C.A. Zeitouni D. et al.Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.Nat Med. 2019; 25: 628-640Crossref PubMed Scopus (315) Google Scholar However, pancreatic cancer cells are able to escape autophagy blockage through an up-regulation of macropinocytosis.7Su H. Yang F. Fu R. et al.Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.Cancer Cell. 2021; 39: 678-693.e11Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Macropinocytosis is a nonselective endocytic process, in which cells engulf extracellular fluid that contains proteins, lipids, and other cell debris. Similar to autophagy, macropinosomes fuse with lysosomes and the cargo is digested by lysosomal hydrolases into distinct building blocks, which are fed back into metabolic pathways.8Lambies G. Commisso C. Macropinocytosis and cancer: from tumor stress to signaling pathways.Subcell Biochem. 2022; 98: 15-40Crossref PubMed Scopus (2) Google Scholar In this issue of Gastroenterology, Zhou et al9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar delineate a fascinating mechanism of how pancreatic cancer cells mobilize the release of nutrients from muscle cells to increase their own metabolite uptake by macropinocytosis. This is of major importance; a high number of patients with pancreatic cancer show cancer cachexia, which manifests in muscle wasting. However, clinical interventions of cancer cachexia remain a challenge.10Kordes M. Larsson L. Engstrand L. et al.Pancreatic cancer cachexia: three dimensions of a complex syndrome.Br J Cancer. 2021; 124: 1623-1636Crossref PubMed Scopus (15) Google Scholar Zhou et al9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar identified the acyl-coenzyme A (CoA) synthetase ACSS2 as a key player in regulating macropinocytosis of pancreatic tumor cells, which simultaneously stimulated the expression of procachectic cytokines and systemically influenced the regulation of muscle wasting markers Atrogin-1 and MuRF1 in muscle cells. In an orthotopic xenograft mouse model, a knockout of ACSS2 in a human cachectic and noncachectic pancreatic cancer cell line resulted in decreased tumor growth. The ACSS2 knockout cancer cell lines revealed strongly reduced proliferation and macropinocytosis in vivo and in vitro. Notably, mice transplanted with the cachectic cell line exhibited a less pronounced cachectic phenotype, when ACSS2 was depleted.9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar It would have been interesting to investigate the influence of autophagy, because it has been described that nuclear ACSS2 regulates epigenetically the expression of autophagy-related genes.11Li X. Yu W. Qian X. et al.Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.Mol Cell. 2017; 66: 684-697.e9Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar The cytosolic ACSS2 enzyme converts exogenous consumed acetate to acetyl-CoA, which is an important metabolic intermediate for fatty acid synthesis (Figure 1). Moreover, acetyl-CoA serves a substrate for protein and histone acetylation to modulate signaling pathways and epigenetic control.12Campbell S.L. Wellen K.E. Metabolic signaling to the nucleus in cancer.Mol Cell. 2018; 71: 398-408Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Indeed, Zhou et al9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar uncovered an epigenetic control of the transcription factor ETV4 via an acetylation of lysine 27 on histone H3 regulating the target gene ZIP4, a zinc transporter involved in macropinocytosis, muscle wasting and epithelial-to-mesenchymal transition of pancreatic cancer cells.13Yang J. Zhang Z. Zhang Y. et al.ZIP4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating RAB27B-regulated release of extracellular vesicles from cancer cells.Gastroenterology. 2019; 156: 722-734.e6Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,14Liu M. Zhang Y. Yang J. et al.Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer.Gastroenterology. 2021; 160: 1771-1783.e1Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar They furthermore identified that the macropinocytosis-associated gene SDC1 is directly activated by the transcription factor CREB1,9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar which might operate in this context in conjunction with the histone acetyltransferases p300 promoting gene expression. Especially under metabolic stress conditions, acetyl-CoA also stimulates an epigenetic activation of genes involved in lipid synthesis,15Gao X. Lin S.H. Ren F. et al.Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia.Nat Commun. 2016; 7: 11960Crossref PubMed Scopus (210) Google Scholar suggesting that a constant demand for lipids by dividing cancer cells for membrane production could be a balanced interplay of fatty acid scavenging through macropinocytosis and de novo lipid synthesis (Figure 1). Nevertheless, a nutrient-poor microenvironment that surrounds pancreatic cancer cells requires further action of the cancer cells to ensure an adequate metabolite uptake. Recent studies have shown distinct ways in which cancer cells guarantee their nutrient supply. One possibility is the uptake of cellular debris from adjacent necrotic cells by macropinocytosis.16King B. Araki J. Palm W. et al.Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis.Genes Dev. 2020; 34: 1345-1358Crossref PubMed Scopus (25) Google Scholar Although tumor necrosis is a common feature of pancreatic cancer and associated with aggressive behavior and a poor outcome,17Hiraoka N. Ino Y. Sekine S. et al.Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation.Br J Cancer. 2010; 103: 1057-1065Crossref PubMed Scopus (83) Google Scholar the link to enhanced macropinocytosis needs further investigations, particularly in vivo. Another possibility of how cancer cells secure their constant nutrient demand was shown by a study from Zhang et al.18Zhang Y. Recouvreux M.V. Jung M. et al.Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness.Cancer Discov. 2021; 11: 1808-1825Crossref PubMed Scopus (26) Google Scholar They uncovered macropinocytosis in the tumor-surrounding cancer-associated fibroblasts (CAFs) under glutamine-deprived growth conditions, which resulted in an increased secretion of amino acids by CAFs to support pancreatic cancer cell growth.18Zhang Y. Recouvreux M.V. Jung M. et al.Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness.Cancer Discov. 2021; 11: 1808-1825Crossref PubMed Scopus (26) Google Scholar Whether the nourishment from neighbor cells is actively induced by pancreatic cancer cells is an exciting aspect to decipher in future studies. Interestingly, Zhou et al9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar suppose that pancreatic cancer cells are able to actively induce a systemic nutrient release from muscle cells. They identified the cytokine, tumor necrosis factor–related apoptosis inducing ligand, TRAIL as a possible procachectic factor that is systemically released from pancreatic cancer cells to stimulate muscle wasting (Figure 1). The activation of metabolite scavenging pathways in pancreatic tumor cells share the common goal of maintaining tumor growth and survival at all costs, even if this means weakening the human organism itself. Targeting macropinocytosis might be, similar to autophagy inhibition, a treatment option for combination cancer therapies. In this context, it needs to be understood whether decreased macropinocytosis activity leads to increased autophagy and vice versa, and whether this influences the formation of cancer cachexia. If evidence accumulates that macropinocytosis is the major cause for cancer cachexia, a disturbed balance between autophagy and macropinocytosis might even predict a cachectic cancer phenotype. Moreover, a combined inhibition of autophagy and macropinocytosis would effectively deplete the nutrient supply of cancer cells. The complexity and specificity of metabolic changes in pancreatic cancer patients holds great promises for diagnosing pancreatic cancer patients in high-risk cohorts. Our own investigations have demonstrated that a blood-derived metabolic biomarker signature discriminates patients with pancreatic cancer and chronic pancreatitis with a high accuracy.19Mayerle J. Kalthoff H. Reszka R. et al.Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis.Gut. 2018; 67: 128-137Crossref PubMed Scopus (147) Google Scholar,20Mahajan U.M. Oehrle B. Sirtl S. et al.Independent validation and assay standardization of improved metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis.Gastroenterology. 2022; 163: 1407-1422Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Overall, Zhou et al9Zhou Z. Ren Y. Yang J. et al.Acetyl-coA Synthetase 2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.Gastroenterology. 2022; 163: 1281-1293Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar expand our knowledge of the complex mechanism of cancer cell macropinocytosis under metabolic stress conditions and the release of tumor-derived factors stimulating muscle wasting and cancer cachexia. Further experimental studies demonstrating important interactions between macropinocytosis, autophagy, and cancer cachexia as parallel or consecutive processes are eagerly awaited. The authors sincerely apologize to investigators whose work was not cited owing to space limitations. Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic CancerGastroenterologyVol. 163Issue 5PreviewACSS2 promotes macropinocytosis and muscle wasting through ETV4/ZIP4- mediated metabolic reprogramming, which provides additional nutrients to support tumor growth in pancreatic cancer. Full-Text PDF