Fig 1: Coordinated reprogramming of ccRCC transcriptome, metabolome and secretome. The expression of genes encoding SPARC, SERPINE1 and STC2 is upregulated while expression of DPP7 is downregulated in ccRCC cells, which reflects altered levels of the encoded protein in the extracellular milieu. The expression of genes encoding proteins involved in protein trafficking and secretion is reprogrammed to support changes in concentrations of extracellular proteins and metabolites: MIA2 (cTAGE5) a receptor of endoplasmic reticulum, localizing to the ER exit sites (ERES), a critical regulator of COPII assembly, protein trafficking and export [33–36]. ANXA3 localizes to endocytic compartments in ccRCC cells [37] and contributes to the regulation of vesicles release [38]. KIF20A is a kinesin crucial for the fission of RAB6-positive vesicles and their exit from Golgi/TGN membranes [27]. It also promotes secretion of factors involved in proliferation of castration-resistant prostate cancer [39]. SYTL3 is a critical effector of RAB27B, enabling kinesin-microtubule-dependent movement of secretory granules towards plasma membrane [40]. ABCA12 is a transmembrane lipid transporter, required for the proper transcriptional programming of vesicle trafficking and cytoskeletal remodeling pathways, lipid raft composition, as well as formation and functioning of secretory granules in pancreatic cells [41]. PCSK5 is a proprotein convertase, which cleaves the target proproteins converting them into their active functional forms. Enhanced expression of SLC16A4 transporter ensures increased secretion of lactate. Changes in concentrations of extracellular proteins (STC2, SPARC, SERPINE1, TGFBI, DPP7, and TF) as well as metabolites affect the functioning of TME cells. TGN: trans-Golgi network; COPII: The Coat Protein Complex II vesicles; Pyr: pyruvate; aKG: a-keto glutarate; PM: plasma membrane; CAFs: cancer-associated fibroblasts; DCs: dendritic cells; ECs: endothelial cells. 4-OH-P: 4-hydroxyproline. Upregulation/downregulation is shown with red/blue font, respectively