物理驱动的染色体不稳定性促使巨噬细胞协同攻击

Extracellular matrix often accumulates in and around solid tumors, and such tumors also evolve diverse mutations that drive cancers, confound therapies, and modulate immune interactions. Across cancer types, we observe chromosome number changes associate with collagen-I levels, and our experiments show rare heritable chromosome losses are induced by a stiff 3D matrix around spheroids. Chromosome reporters (ChReporters) reveal losses in as few as ~0.1% of cells, with a mechanism in spheroids based on distortion of mitotic spindles - which increases with knockdown of the candidate tumor suppressor myosin-II. Chromosomes mis-segregate into micronuclei that increase with matrix stiffness despite suppressed cell division. Drugs that increase micronuclei in 2D and that rely on an unperturbed spindle show no effect in 3D where the spindle is perturbed. Tumors in vivo that are surrounded by stiff collagen likewise show more but varied chromosome loss and slower growth than 2D cultures. High variance of ChReporter-negative colonies further illustrate increased heterogeneity with 3D matrix stiffness and heritable mutations per Luria-Delbruck theory. Physical learning models of evolving chromosome numbers in proliferating cells are developed and fit key statistical trends.Temperature is another physical stressor - as solid tumors tend to be warm - and we show it has similar outcomes as matrix physical properties. Heating is also now part of various therapies as are immune-engineering approaches. We take advantage of Macrophages that often pervade solid tumors where clusters of macrophages are sometimes seen and associate with longer survival of patients. However, clustering mechanisms, responses to stressor above, and impacts on key functions such as phagocytosis remain obscure. Under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term “intrudopodia.” Cluster formation is favored by M1 macrophages after exposure to interferons and T cell-derived cytokines. M1 macrophages upregulate specific cell-cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation and unleashing pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions-at least when phagocytosis conditions are maximized by checkpoint disruption and other strategies. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Cooperative phagocytosis thus overcomes solid tumor cohesion-and might explain why the macrophage clustering factor ITGAL associates with patient survival.