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.

中文翻译：

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对空间不同基质细胞的多组学分析揭示了肿瘤诱导的侵袭性肿瘤边缘成纤维细胞中 CDK4-pRB 轴的 O-糖基化


侵入性前沿代表了肿瘤转移的潜在门户。肿瘤边缘的成纤维细胞在促进癌症侵袭和转移中的作用尚未得到全面阐明。我们假设肿瘤微环境（TME）内肿瘤和基质细胞之间的串扰导致关键生物途径的激活，具体取决于它们在肿瘤中的位置（边缘与核心）。在这里，我们强调了从人肺腺癌中建立的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。使用包括基因组学、蛋白质组学和 O-糖蛋白质组学的多组学方法来表征 TAF 和癌细胞之间的串扰。这些分析表明，O-糖基化是糖代谢产生的一种重要的翻译后修饰，它改变了关键的生物途径，包括基质中的细胞周期蛋白依赖性激酶 4 和磷酸化视网膜母细胞瘤蛋白 (CDK4-pRB) 轴，并间接调节促侵袭特征癌细胞。总之，O-糖蛋白质组代表了对肿瘤-基质串扰所涉及的重要生物过程的新考虑，也是提高 CDK4 抑制剂抗癌功效的潜在途径。