Effect of sex-related non-immune cell crosstalk in the tumor microenvironment on skeletal muscle loss in colorectal cancer.

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Background: Colorectal cancer (CRC) progression is influenced by multiple risk factors, including sex-based differences in tumor biology and the tumor microenvironment. A critical component of this microenvironment is skeletal muscle, which undergoes significant wasting in cancer patients, contributing to poor prognosis. Approximately 35% of CRC patients experience muscle loss, with female patients exhibiting lower skeletal muscle mass and body mass index (BMI) compared to males. However, the molecular mechanisms underlying these sex-specific differences remain poorly understood. Methods: We hypothesize that sex-specific differences in CRC cell transcriptomes and secretomes contribute to distinct tumor–muscle interactions, with female-derived CRC cells exhibiting unique molecular signatures that accelerate skeletal muscle loss. Our transcriptomic analysis of nine CRC cell lines derived from male and female patients revealed significant sex-dependent gene expression differences. Results: We identified 13 genes uniquely expressed in female-derived CRC cells, 177 genes with at least two-fold higher expression in female CRC cells compared to male CRC cells, and 537 genes significantly downregulated in female CRC cells. Notably, mitochondrial tRNAs (mt-tRNAs) were upregulated in female-derived CRC cells, suggesting a role in metabolic regulation and tumor-microenvironment interactions. Additionally, secretome profiling revealed that female CRC cells secrete distinct factors, including CCL15, AZGP1, and RNASET2, which may differentially modulate skeletal muscle metabolism and immune responses. Specifically, we propose that mt-tRNA upregulation and differential cytokine secretion in female CRC cells play a key role in exacerbating cancer-associated muscle wasting. Conclusions: This study will provide mechanistic insights into sex-based differences in CRC progression, identify novel biomarkers for early detection, and inform therapeutic strategies to mitigate muscle loss in CRC patients. Our findings could contribute to the development of sex-specific interventions aimed at improving CRC patient outcomes.