(959.11) The LP07 and LLC pre-clinical models of lung cancer present divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting

Poster Board Number: E610

Daniel Belcher (Penn State University), Maria de la Rosa Guitart (Universitat Pompeu Fabra, CIBERES), Brian Hain (Penn State University), Hyo-Gun Kim (Penn State University), David Waning (Penn State University), Esther Barreiro (Universitat Pompeu Fabra, CIBERES), Gustavo Nader (Penn State University)

Abstract

Pre-clinical models of lung cancer have been instrumental in uncovering the mechanisms of muscle wasting. However, differences in genetic background, immune status, tumor origin, and administration route can introduce confounding variables, limiting the understanding of muscle wasting in lung cancer. In this study, we examined anabolic deficits and the expression of pro-inflammatory cytokines in the skeletal muscle of LP07 and Lewis lung-cell carcinoma (LLC) pre-clinical models of lung cancer. Female mice were injected with either LP07 or LLC tumor cells in their right flank. Tumor growth occurred over a 28–30-day period and resulted in gastrocnemius muscle depletion with more pronounced wasting in the LLC model (LP07: -20.3%, P=0.004; LLC: -31.9%, Plt;0.001). The LP07 mice experienced a loss in ribosomal (r) RNA (-34.9%, P=0.015), which was likely due to decreased rDNA transcription elongation, evidenced by a lower internal transcribed spacer (ITS) signal (-47.9%, P=0.017). Reductions in RPS6 (LP07: -60.8%, P=0.020; LLC: -83.0%, P=0.003) and 4E-BP1 (LP07: -31.4%, Plt;0.001; LLC: -36.5%, Plt;0.001) phosphorylation was similar in both models but was independent of changes in mTOR phosphorylation which was less pronounced in the LP07 (-2.8%, P=0.997) compared with the LLC model (-44.2%, P=0.042). Additionally, IL-6 and TNF-α mRNA levels were similarly elevated in the LLC (IL-6: 750.7%. Plt;0.001; TNF-α: 156.5%, Plt;0.001) and LP07 models (IL-6: 719.4%, Plt;0.001; TNF-α: +100.0%, P=0.28). In summary, while both models underwent muscle depletion, only the LP07 model displayed a reduction in rRNA and rDNA transcription. RPS6 and 4E-BP1 phosphorylation’s were similar in both models, however, the increase in pro-inflammatory factors was more pronounced in the LLC model. Our findings reveal a significant divergence in the anabolic deficits and expression of pro-inflammatory effectors of muscle wasting in the LP07 and LLC pre-clinical models of lung cancer.

NIH AR-073385 and AR-078430 (GAN)