小细胞肺癌 (SCLC) 肿瘤由不同的细胞亚群组成，包括神经内分泌 (NE) 和非神经内分泌 (non-NE) 细胞。虽然非 NE SCLC 细胞的分泌因子已被证明可以支持 NE 细胞的生长，但潜在的分子因素尚不清楚。在这里，我们发现非 NE SCLC 细胞分泌的外泌体型小细胞外囊泡（SEV）可促进 NE SCLC 细胞的粘附和存活。纯化的 SEV 的蛋白质组学分析表明，非 NE 细胞的 SEV 中高度富集细胞外基质 (ECM) 蛋白和整合素，而从 NE 细胞纯化的 SEV 中富集核酸结合蛋白。添加在纯化的细胞外囊泡 (EV) 中鉴定的精选纯化 ECM 蛋白，特别是纤连蛋白、层粘连蛋白 411 和层粘连蛋白 511，能够替代非 NE 衍生的 SEV 在促进 NE SCLC 细胞粘附和存活中的作用。这些相同的蛋白质在人类 SCLC 亚型中差异表达。这些数据表明，非 NE 细胞分泌的携带 ECM 的 SEV 在支持 NE SCLC 细胞的生长和存活中发挥着关键作用。© 2023 Wiley-VCH GmbH。

Small cell lung cancer (SCLC) tumors are made up of distinct cell subpopulations, including neuroendocrine (NE) and non-neuroendocrine (non-NE) cells. While secreted factors from non-NE SCLC cells have been shown to support the growth of the NE cells, the underlying molecular factors are not well understood. Here, we show that exosome-type small extracellular vesicles (SEVs) secreted from non-NE SCLC cells promote adhesion and survival of NE SCLC cells. Proteomic analysis of purified SEVs revealed that extracellular matrix (ECM) proteins and integrins are highly enriched in SEVs of non-NE cells whereas nucleic acid-binding proteins are enriched in SEVs purified from NE cells. Addition of select purified ECM proteins identified in purified extracellular vesicles (EVs), specifically fibronectin, laminin 411, and laminin 511, were able to substitute for the role of non-NE-derived SEVs in promoting adhesion and survival of NE SCLC cells. Those same proteins were differentially expressed by human SCLC subtypes. These data suggest that ECM-carrying SEVs secreted by non-NE cells play a key role in supporting the growth and survival of NE SCLC cells.© 2023 Wiley-VCH GmbH.