Osteosarcoma pulmonary metastasis: the hemodynamic mechanical-filtration hypothesis for subpleural predominance.

Background: Pulmonary metastasis remains the leading cause of death in osteosarcoma; however, the pronounced and long-recognized subpleural predominance of metastatic nodules remains mechanistically unexplained. Contemporary "seed-and-soil" and pre-metastatic niche frameworks emphasize microenvironmental conditioning and spatial heterogeneity, but they do not explain why metastatic seeding consistently localizes to the peripheral 1-2 cm of the lung. Likewise, modern mechanical perspectives acknowledge that circulating tumor cells can be retained at multiple sites within the pulmonary microvasculature (including capillaries and pre-capillary arterioles), yet they do not account for a reproducible intra-organ, subpleural spatial bias. Knowledge gap: A testable model that links pulmonary microvascular geometry and hemodynamics to the consistent subpleural localization of early osteosarcoma metastatic seeding has yet to be established. Hypothesis: We propose the Hemodynamic Mechanical-Filtration Hypothesis: a clinically relevant subset of osteosarcoma circulating material may travel as larger, relatively stiff embolic units, including circulating tumor cell clusters (CTC clusters) and/or complex aggregates involving platelets and fibrin (CTC-platelet aggregates). Because these units have less instantaneous deformability than single cells, they may undergo size-selective mechanical arrest in terminal pre-alveolar arterioles (20-40 μm), which constitute a functional bottleneck immediately proximal to the capillary bed. We further hypothesize that filtration-prone distal arteriolar segments are preferentially distributed within a defined subpleural distance, an explicitly testable quantitative anatomical premise. This initial mechanical arrest establishes a spatial template for seeding, upon which post-arrest metastatic niche maturation and outgrowth can proceed, potentially modulated by upstream pre-metastatic niche (PMN) priming. Approach: The hypothesis integrates pulmonary microvascular anatomy, tumor biomechanics, cluster/aggregate rheology, and hemodynamic gradients. We outline falsifiable predictions and multi-level validation strategies, including intravital imaging, compliant/endothelialized microfluidic models, computational flow simulations, and clinical spatial mapping of metastatic nodules as a function of distance from the pleura. Key insights: By explicitly coupling embolic physical properties with hierarchical vascular geometry and regional hemodynamics, this framework provides a spatially resolved extension of mechanical arrest models and generates testable explanations for subpleural predominance as well as for the conditions under which the site of arrest may shift. Significance: If validated, this hypothesis would reframe early osteosarcoma lung seeding as a process constrained by microvascular biomechanics and could guide future mechanistic studies aimed at developing preventive strategies targeting embolic integrity and pulmonary microcirculatory conditions.