Hypoxia-Induced Active Dynamics Promotes Early Tumorigenesis

Abstract

Understanding early tumor formation provides insights for cancer prevention. However, in vivo studies focus on later stages, leaving initial tumorigenesis poorly understood. Hypoxia is a key microenvironmental factor in cancer, yet its impact on single-cell tumor initiation and dynamics remains unclear. To address this, we developed an integrated live-imaging platform for hypoxic conditions, enabling first direct observation of 3D tumor spheroid development from a single cell. We show hypoxia accelerates tumorigenesis. Beyond growth, directional movement promotes spheroid fusion. This is driven by optimized actin polymerization and cell-cell adhesion. Hypoxia induces specialized, fusion-competent cells with outstretched F-actin and tiny nuclei that bridge spheroids. Concurrently, hypoxia triggers genetic instability, evidenced by tiny nuclei and aneuploidy. The interplay between dynamic and genetic instability optimizes spheroid mechanical properties, creating a positive feedback loop fuels proliferation. Our findings offer insight into hypoxias role in early tumorigenesis and highlight potential of targeting dynamic-genetic balance for prevention. Statement of SignificanceHypoxia accelerates early tumorigenesis by promoting directional 3D tumor spheroid fusion via optimized actin dynamics and mechanical balance, while inducing micronuclei formation and aneuploidy-linked genetic instability, forming a positive feedback loop that boosts proliferation and malignant progression.