Genome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Cancer Gene Ther. 2024 Jan;31(1):158-173. doi: 10.1038/s41417-023-00693-0. Epub 2023 Nov 21.
MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy.
间充质干细胞（mesenchymal stem cells，MSCs）负责组织修复，很少与体细胞发生细胞融合。在这里，我们表明，在共培养中，约 5%的膀胱癌细胞（UMUC-3）与骨髓来源的间充质干细胞（BM-MSC）融合，并保持高致瘤性。在已经建立的 11 个融合细胞克隆中，膀胱癌细胞携带的 Mb 级缺失在融合细胞中大多缺失，但癌细胞带来的拷贝数增益仍然存在。融合细胞表现出具有 3 极纺锤体的有丝分裂细胞的增加群体，表明基因组不稳定。它们在体外生长更快，在软琼脂中的无锚定生长测定中表现出比亲本 UMUC-3 更高的集落形成能力。融合细胞在异种移植实验中，与亲本 UMUC-3 一样，在 4 周的时间滞后后有效地形成肿瘤。鉴定出 264 个表达特异性改变的基因。其中许多是干扰素刺激基因（ISG），但激活方式与干扰素无关。在它们中，我们表明 PD-L1 在融合细胞中被诱导，其敲除会降低异种移植模型中的肿瘤发生。PD-L1 的诱导方式独立于已知调节 PD-L1 表达的 STAT1，但受组蛋白修饰调节，可能会抑制 PD1 表达的巨噬细胞吞噬作用，从而保护癌细胞免受免疫攻击。融合细胞过度表达多种细胞因子，包括 CCL2，通过将浸润的巨噬细胞转化为肿瘤相关巨噬细胞（TAM）来促进肿瘤进展。这些结果提出了细胞融合促进肿瘤发生的机制，揭示了细胞融合与 PD-L1 之间的新联系，并强调了癌症免疫疗法的疗效。
