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BMES High School Student Chapter Member

HS Poster

Poster 40 - Chemokine-Driven Muscle Wasting in Cancer Cachexia: Therapeutic Insights from 3D Colorectal Cancer Spheroid Models

Saturday, October 26, 2024
10:00 AM – 12:00 PM EST
Location: Exhibit Hall E, F & G

Introduction: Cancer cachexia is a multifactorial syndrome characterized by severe body weight loss, primarily due to the depletion of skeletal muscle mass, which significantly impacts patient morbidity and mortality. Unlike simple starvation, cachexia is marked by an ongoing loss of muscle that cannot be fully reversed by conventional nutritional support, distinguishing it as a critical issue in cancer care. This syndrome is particularly prevalent in patients with advanced malignancies, including colorectal cancer (CRC), where it contributes to poorer treatment outcomes and reduced survival rates. The pathophysiology of cancer cachexia is complex and involves a combination of systemic inflammation, metabolic alterations, and tumor-derived factors that collectively drive muscle wasting. Pro-inflammatory cytokines and tumor-secreted chemokines play pivotal roles in this process, promoting a catabolic state that leads to the degradation of muscle proteins. Our previous study on CRC spheroids demonstrated that 3D spheroid models offer a more physiologically relevant platform for studying tumor behavior. This study focuses on understanding the role of cancer cachexia in muscle wasting through the use of 3D spheroid models derived from CRC cells.

Materials and

Methods: We fabricated two-dimensional (2D) and three-dimensional (3D) CRC spheroid models using murine colon cancer cells (CT26) with the same number of cells, and then compared the effects of these models on cytokine and chemokine secretion using quantitative polymerase chain reaction (qPCR) and ELISA. To evaluate their subsequent impact on muscle cells, we cultured C2C12 muscle tissues and subjected them to cytokines and chemokines sourced from both 2D and 3D platforms. A comprehensive comparative analysis of the gene expression associated with atrophy in muscle cells, subsequent to chemokine treatment in both two-dimensional and three-dimensional environments, was also performed.

Results, Conclusions, and Discussions: Results and Discussions: Notably, key chemokines such as CCL5, CXCL12, CXCL10, and CXCL1 were upregulated in 3D environments, indicating robust interactions with their corresponding receptors (Fig. 1, a and b). Additionally, the expression of established cytokines such as SCF, LIF, IL-6, and IFNγ was assessed (Fig. 1c), with mRNA levels notably elevated in 3D cultures, enhancing cellular functionality and better mimicking in vivo conditions. With these data, ELISA analysis, and information from the literature, we identified four key signaling pathway pairs: CCL5-CCR5, CXCL12-CXCR4, CXCL1-CXCR2, and CXCL10-CXCR3 (Fig. 2). Next, we performed a comprehensive comparative analysis of the gene expression associated with atrophy in muscle cells, subsequent to chemokine treatment in both 2D and 3D environments. Treatment with 3D cancer model supernatants displayed elevated expression of atrophy-related genes in muscle tissue compared to the 2D model, in alignment with the enhanced chemokine secretion of the 3D model (Fig. 3). To assess the contribution of the identified key signaling pathways to cancer cachexia-mediated muscle atrophy, we treated supernatant-exposed muscle chips with the CCL5-CCR5 inhibitor TAK-779 (Fig. 3). The inhibitor in the supernatant treatment normalized muscle atrophic gene expressions, suggesting the therapeutic potential of chemokine receptor blockers for muscle atrophy.

Conclusion: This study highlights the critical role of tumor-derived chemokines in cancer cachexia and their impact on muscle wasting, emphasizing the importance of 3D spheroid models in understanding these complex interactions. The upregulation of chemokines and cytokines in 3D models more accurately reflects the in vivo environment, offering insights into cachexia mechanisms. Key pathways, such as CCL5-CCR5, and the normalization of muscle atrophy genes with targeted inhibitors, suggest that chemokine receptor blockers could be a promising strategy to mitigate muscle atrophy in cancer cachexia. Future research should validate these pathways in clinical settings and explore additional targets for comprehensive treatment.

Acknowledgements (Optional): We would like to express our sincere gratitude to Dr. Young Hoon Son and Dr. Jihee Won for their invaluable support, training, and guidance throughout the course of this study.

References (Optional):