Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomic analysis of tumor-infiltrating NK cells from mifepristone-treated and vehicle-treated LLC-OVA tumor–bearing mice

ABSTRACT: LLC-OVA lung carcinoma cells were used to establish subcutaneous tumors in C57BL/6J mice. One million LLC-OVA cells were injected subcutaneously into each mouse. Tumor-bearing mice were divided into two treatment groups: three mice received mifepristone (60 mg/kg body weight) administered via oral gavage on alternate days, and four mice received vehicle control (olive oil) on the same schedule. Treatments were continued for 18 days. On day 19, mice were sacrificed and tumors were harvested for immune profiling. Tumor-infiltrating NK cells were isolated and subjected to bulk RNA-sequencing to assess transcriptional changes induced by glucocorticoid receptor antagonism within the tumor microenvironment.

INSTRUMENT(S): Illumina NovaSeq 6000, Novogene in-house automated library preparation system

ORGANISM(S): Mus musculus

SUBMITTER: SOURA CHAKRABORTY

PROVIDER: E-MTAB-16381 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Transcriptomic analysis of tumor-infiltrating NK cells from mifepristone-treated and vehicle-treated LLC-OVA tumor–bearing mice

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