Gray Justin M, Park Woo Yong, Holewinski Ronald J, Andresson Thorkell, Carmona-Rivera Carmelo, Kaplan Mariana J, Yang Li
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA.
Sci Rep. 2025 Aug 1;15(1):28054. doi: 10.1038/s41598-025-11807-z.
Understanding mechanisms of cancer cell death and the resulting effect on disease progression is crucial in cancer biology and the insight will likely offer better options for therapeutic treatment. Nuclear expulsion occurs in apoptotic cancer cells in a peptidylarginine deiminase 4 (Padi4) dependent manner. The resulting tumor cell nuclear expulsion product (TuNEP) promotes the outgrowth of neighboring cancer cells through chromatin-bound protein complexes. It is not clear what the protein compositions and functionalities are in these TuNEPs. In this study, we performed extensive proteomic profiling and identified key TuNEP protein components from mouse and human breast cancer cells as well as human lung cancer cells (4T1, MDA-MB-231, and PC9). We further compared TuNEP- specific proteins with those from apoptotic bodies or NETs from neutrophils. We found an enrichment of cellular adhesion molecules as well as increased citrullination of proteins associated with RNA binding. We showed that cellular adhesion molecules integrin and basigin (BSG) promote the growth of tumor spheroids. Our work revealed the unique TuNEP protein components distinct from neutrophil-derived NETs and shed light on potential mechanisms by which these cancer cell-derived TuNEPs promote tumor progression.
了解癌细胞死亡机制及其对疾病进展的影响在癌症生物学中至关重要，这一见解可能为治疗提供更好的选择。核排出以肽基精氨酸脱亚氨酶4（Padi4）依赖的方式发生在凋亡癌细胞中。由此产生的肿瘤细胞核排出产物（TuNEP）通过染色质结合蛋白复合物促进邻近癌细胞的生长。目前尚不清楚这些TuNEP中的蛋白质组成和功能是什么。在本研究中，我们进行了广泛的蛋白质组学分析，从小鼠和人类乳腺癌细胞以及人类肺癌细胞（4T1、MDA-MB-231和PC9）中鉴定出关键的TuNEP蛋白质成分。我们进一步将TuNEP特异性蛋白质与来自凋亡小体或中性粒细胞的中性粒细胞胞外陷阱（NETs）中的蛋白质进行了比较。我们发现细胞粘附分子富集以及与RNA结合相关的蛋白质瓜氨酸化增加。我们表明细胞粘附分子整合素和基底膜蛋白（BSG）促进肿瘤球体的生长。我们的工作揭示了与中性粒细胞来源的NETs不同的独特TuNEP蛋白质成分，并阐明了这些癌细胞来源的TuNEP促进肿瘤进展的潜在机制。
