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ABSTRACT: Transcriptome Alterations of Subcutaneously Inoculated LLC Tumor Tissue from C57BL/6 Mice

PROVIDER: PRJNA977410 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24762918_1.fastq.gz	Fastqsanger.gz
	SRR24762918_2.fastq.gz	Fastqsanger.gz
	SRR24762919_1.fastq.gz	Fastqsanger.gz
	SRR24762919_2.fastq.gz	Fastqsanger.gz
	SRR24762920_1.fastq.gz	Fastqsanger.gz

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Project description:Cachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced cancer. RAGE (receptor for advanced glycation end-products) signaling in mice sustains hallmarks of cancer cachexia (CC), including inflammation, the release of tumor-derived CC factors, and skeletal muscle catabolism. Indeed, mice lacking RAGE (Ager−/− mice) showed delayed loss of muscle mass and strength and dramatically increased survival. Here, we investigated the specific contribution to CC of RAGE expressed at tumor and muscle level by using: i) WT and Ager−/− mice subcutaneously injected with LLC (Lewis lung carcinoma) cell clones stably transfected with full-length (fl) RAGE, RAGEΔcyto (a non-transducing form of RAGE) or empty vector; and, ii) a newly generated tamoxifen-inducible conditional AgermKO mouse model, in which the RAGE gene is selectively deleted in skeletal muscles, injected with LLC cells. We found that: i) modulation of RAGE expression in LLC clones did not alter their cachectic potential; ii) Ager−/− mice did not activate muscle catabolism irrespective of the injected LLC clone, suggesting that RAGE overexpression in the tumor is not sufficient per se to induce muscle atrophy; and, iii) LLC-injected AgermKO mice showed increased survival, maintenance of muscle performance, resistance to the loss of body, muscle mass and performance, and reduced circulating CC factors compared with LLC-bearing control (Agerflox) mice. An increase in hybrid myofibers expressing both slow and fast MyHC isoforms characterized muscles of LLC-AgermKO . Different and unexpected proteomic signatures were found in muscles of tumor-bearing mice in dependence on RAGE expression and thirty-five proteins emerged as modulated in common in LLC/AgermKO and LLC/Ager–/– vs LLC/Agerflox mice suggesting novel mechanisms involved in the resistance against CC. Thus, RAGE engagement at myofiber rather than tumor level is a determinant in sustaining CC. Nevertheless, total ablation of the receptor maximally protects against cancer-induced muscle wasting, indicating that systemic targeting of RAGE might represent a promising strategy to counteract the cachexia syndrome in cancer patients.

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