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Effects of Simulated Microgravity on Colorectal Cancer Organoids Growth and Drug Response

ABSTRACT: Cellular and molecular dynamics of human cells are constantly affected by gravity. Alteration of the gravitational force disturbs the cellular equilibrium, which might modify physiological and molecular characteristics. Nevertheless, biological responses of cancer cells to reduced gravitational force remains obscure. Here, we aimed to comprehend not only transcriptomic patterns but drug responses of colorectal cancer (CRC) under simulated microgravity. We established four organoids directly from CRC patients, and organoids cultured in 3D clinostat were subjected to genome wide expression profiling and drug library screening. Our observations revealed changes in cell morphology and an increase in cell viability under simulated microgravity compared to their static controls. Transcriptomic analysis highlighted a significant dysregulation in the TBC1D3 family of genes. The upregulation of cell proliferation observed under simulated microgravity conditions was further supported by enriched cell cycle processes, as evidenced by the functional clustering of mRNA expressions using cancer hallmark and gene ontology terms. Our drug screening results indicated an enhanced response rate to 5-FU under conditions of simulated microgravity, suggesting potential implications for cancer treatment strategies in simulated microgravity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271642 | GEO | 2024/09/11

REPOSITORIES: GEO

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Project description:Gravitational biology and its effects on cancer cells are of great interest, especially today that space is more accessible than ever. Despite advances in space research, little is known about the impact of microgravity on tumor and its biology and data from the literature are often contradictory due to different setup, experimental designs and analyzed time-points. Exploiting the Random Positioning machine we evaluated on pancreatic cancer cells the effects of long-term exposure to simulated microgravity (SMG) performing a large proteomic, lipidomic and transcriptional analysis at 1, 7 and 9 days. Results indicate that SMG affects cellular morphology through a time-dependent activation of “Regulation of actin-based motility by Rho”and “Cdc42” pathways that contribute to the dynamic actin rearrangement involved in the formation of 3D spheroidal structures and in the enhancement of epithelial-to mesenchymal transition. To support energy stress remediation and counteract massive apoptosis activation and cell proliferation inhibition, induced by SMG, tumor cells downregulate the protein translational machinery, and undergo a metabolic reprogramming orchestrated by the activation of HIF-1a and PI3K/Akt pathways. These two pathways pave the way for glucose metabolism encouraging upregulation of glycolysis, mitochondrial activity, Tri-carboxylic acid cycle and fatty acid synthesis (rather than B oxidation), suggesting a de novo synthesis of triglycerides involved in the formation of membrane lipid bilayer and signaling mediators. This metabolic plasticity, typical of cancer stem cells, is in accordance with the SMG-mediated activation of PI3K/Akt/NFkB/ERK5/IL-8 signaling axis that significantly upregulates the expression of stem-associated proteins and expansion of cancer stem cells with a more mesenchymal phenotype and improved migratory capability. Altogether, our findings clearly indicate that microgravity induces cancer cell transformation towards the acquisition of cancer stem cell-like features, with a more aggressive and metastatic potential and pave the base for future study of response to anti neoplastic drugs under simulated microgravity.

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Effects of Simulated Microgravity on Colorectal Cancer Organoids Growth and Drug Response

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