Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma

Abstract

Background Besides featured glucose consumption, recent studies reveal that cancer cells might prefer “addicting” specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear. Methods Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved. Results We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD. Conclusion Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.

Integrating single-cell and bulk RNA sequencing to develop a cancer-associated fibroblast-related signature for immune infiltration prediction and prognosis in lung adenocarcinoma

“…CAFs play a significant role in tumor progression by secreting various factors, such as growth factors, extracellular matrix proteins, and immunosuppressive ligands, which also contribute to the immunosuppressive effects of the TME ( 40 ). In LUAD, CAFs promote cancer progression by enhancing glutamine uptake in LUAD cells through CAF-specific long-chain non-coding RNA LINC01614 packaged in secreted exosomes ( 41 ). Furthermore, the reduction of extracellular CLCN3 secretion via HNRNPK knockdown inhibits CAF activation and TGF-β1 production.…”

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment

“…Glycolysis↑ OXPHOS↓ ECM acidification↑ [257] Tumor cell GC Lipid-ROS↓ Ferroptosis ↓ [258] Tumor cell BC Glycolysis↑ OXPHOS↓ Proliferation↑ [259] Tumor cell HCC Glycolysis↑ Migration, invasion↑ [260] Tumor cell LUAD Glutamine uptake↑ Tumorigenesis↑ [261] Tumor cell BC Glycolysis↑ HTR↑ [262] Tumor cell BC Glycolysis↑ OXPHOS↓ Tumorigenesis↑ [263] Tumor cell Laryngeal cancer Glycolysis↑ Proliferation↑ [264] Tumor cell BC Glycolysis↑ Apoptosis↓ [265] Tumor cell Melanoma FAO↑ Migration↑ [266] Tumor cell HCC GLUT-1↑ 5-FU resistance↑ [267] Tumor cell NPC Lipid accumulation↑ Proliferation, migration↑ [268] tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of Kyn, which ultimately activate AKT and STAT3 signaling pathways and induce chemoresistance [237]. (Table 3).…”

“…CAFs can regulate amino acid metabolism in lung adenocarcinoma (LUAD) cells via exosomes. CAFs-derived exosomal LINC01614 can interact with ANXA2, p65 and activate NF-κB pathway to promote the expression SLC38A2 and SLC7A5, thus enhancing tumor cells glutamine uptake [261]. Furthermore, CAFs-derived exosomal mtDNA may regulate hormonal therapy-resistant (HTR) in breast cancer patients.…”

Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment

“…LncRNAs also participate in activation of LNFs to CAFs, whereas activated CAFs can change gene expression and secretion characteristics of NSCLC cells through lncRNAs [73]. Liu et al screened fibroblast-specific lncRNAs using RAN-seq data and identified LINC01614 promoting the secretion of IL-6 from cancer cells that upregulates LINC01614 in CAFs, constituting a feedforward loop between CAFs and NSCLC cells [74].…”