Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4-pRB Axis in Fibroblasts at the Invasive Tumor Edge.
Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4-pRB Axis in Fibroblasts at the Invasive Tumor Edge.
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DOI：
10.1158/0008-5472.can-21-1705
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发表时间：
2022-02-15
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影响因子：
11.2
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侵袭性前沿是肿瘤转移的潜在途径。来自肿瘤边缘的成纤维细胞在促进肿瘤侵袭和转移中的作用尚未全面阐明。我们假设，肿瘤和肿瘤微环境(TME)中的间质细胞之间的串扰导致关键生物通路的激活，这取决于它们在肿瘤中的位置(边缘与核心)。在这里，我们强调了来自侵袭性边缘的肿瘤邻近成纤维细胞(TAF)和来自肿瘤核心的肿瘤核心成纤维细胞(TCF)之间的表型差异，这是从人类肺腺癌建立的。一种包括基因组学、蛋白质组学和O-糖蛋白组学的多组学方法被用来表征TAFs和癌细胞之间的串扰。这些分析表明，O-糖基化是糖代谢引起的一种重要的翻译后修饰，改变了主要的生物学途径，包括间质中的细胞周期蛋白依赖激酶4和磷酸化视网膜母细胞瘤蛋白(CDK4-PRB)轴，并间接调节癌细胞的亲侵袭特性。综上所述，O-糖蛋白组学为肿瘤-间质串扰的重要生物学过程提供了新的思路，也为提高CDK4抑制剂的抗癌效果提供了一条新的途径。
The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.