Exposure of tumor cells to microgravity, whether aboard space platforms or in ground-based simulators profoundly remodels their biology, affecting mechanotransduction, epigenetic regulation, three-dimensional architecture and intercellular communication [1]. In colorectal cancer organoids cultured in a 3D clinostat, cells adopt quiescent-cystic morphologies, hyperactivate mitotic-spindle, G2/M-checkpoint and E2F-target pathways and lose expression of TBC1D3 GTPases, doubling their proliferation rate versus 1G controls [2].

By contrast, A-172 glioblastoma lines on a 3D “microgravity-on-a-chip” exhibit smoother cell borders, reduced filopodia and lamellipodia, and inactivation of Hippo signaling—with YAP-1 down 22 % and vinculin down 20 %, culminating in suppressed growth [3]. Epigenetically, microgravity suppresses histone-deacetylase genes (HDACs) and core histones (H2B, H4, H2A) and lowers KMT2C/D/E methyltransferases, implicating genomic instability and impaired DNA repair in both colorectal and breast (MCF-7) aggregates [2,4].

Moreover, adherent cells shed into suspension spontaneously form multicellular spheroids that mimic micrometastases, displaying oxygen gradients, reduced central necrosis and differential chemosensitivity; notably, colorectal spheroids under microgravity show enhanced 5-fluorouracil efficacy, suggesting more predictive drug screens [2,4]. Exosome biogenesis is also reprogrammed: MDA-MB-231 breast cells release fewer but larger vesicles enriched in Ras-like GTPases (Ral, Rho, CDC42), modulating paracrine invasiveness, while FTC-133 thyroid cells on the ISS elevate CD63/CD81 exosomal markers and alter over 100 microRNAs tied to aggressiveness, yielding novel epigenetic targets [1].

Lineage-specific responses further illustrate microgravity’s heterogeneity: A549 lung carcinoma regains E-cadherin and downregulates N-cadherin/MMP2 toward a more epithelial phenotype; PC-3 prostate spheroids show anomalous divisions, early inflammatory signals (↑IL-6, ↑CXCL8) and RPM spheroids with upregulated VEGF, integrins and cytoskeletal components endorsing angiogenesis; gastrointestinal models shift to glycolytic metabolism and modulate multidrug-resistance genes; and melanoma (HaCaT/A375) increases viability and mitochondrial activity but reduces proliferation with actin network reorganization [5].

Collectively, these findings demonstrate that microgravity redefines tumor cell behavior, provides three-dimensional models closely emulating human cancers and accelerates therapeutic target discovery and preclinical drug evaluation, establishing microgravity research as a promising catalyst in translational oncology.

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