Mus musculus Transcriptome or Gene expression

To investigate the paracrine effects of stromal elements on cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic cultures amenable to functional genomics and metabolomics. Here we show that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the cancer epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways. Finally, we implicate the BET family of epigenetic readers as key transducers of stromal inputs to drive alterations in gene expression. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.

为探究基质成分对癌细胞的旁分泌效应，我们构建了一套「基质」共培养体系，该体系将结构性及可扩散性的基质源性组分纳入可用于功能基因组学（functional genomics）与代谢组学（metabolomics）研究的同型培养模型中。本研究证实，肿瘤微环境信号可协同调控癌细胞代谢与基因表达。基质信号广泛调控癌细胞表观基因组中的组蛋白乙酰化水平，这一变化与合成代谢及炎症相关基因的诱导表达密切相关。基质因子诱导的基因表达与代谢变化，与此前报道的致癌性Kras（oncogenic Kras）激活后所产生的变化高度重合，这提示细胞自主性通路与微环境通路之间存在功能互补性。最后，我们证实表观阅读蛋白BET家族（BET family）是介导基质信号调控基因表达改变的关键转导因子。本研究表明，旁分泌表观基因组调控是基质信号驱动癌细胞代谢与免疫适应恶劣肿瘤微环境的关键通路。