Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer.
Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer.
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DOI：
10.1186/s13073-023-01236-w
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发表时间：
2023-11-17
期刊：
影响因子：
12.3
通讯作者：
Gentles, Andrew J.
中科院分区：
文献类型：
--
作者：
Brennan, Kevin;Espin-Perez, Almudena;Chang, Serena;Bedi, Nikita;Saumyaa, Saumyaa;Shin, June Ho;Plevritis, Sylvia K.;Gevaert, Olivier;Sunwoo, John B.;Gentles, Andrew J.
关键词：
头颈癌（HNC）患者的预后很差，近几十年来几乎没有改善，部分原因是缺乏治疗选择。为了确定有效的治疗靶点，我们通过对转录组学数据的大规模系统分析，试图确定驱动转移和HNC进展的分子途径。我们对29项基因表达研究进行了荟萃分析，其中包括2074例原发性HNC活检，以确定与生存和淋巴结转移（LNM）相关的基因和转录途径。为了了解这些基因在HNC中的生物学作用，我们通过整合来自分选细胞群的单细胞RNA-seq和大量RNA-seq，确定了它们相关的癌症途径，以及在HNC肿瘤微环境中表达它们的细胞类型。患者生存相关基因是异质的，包括多种肿瘤生物学过程的驱动因素：这些过程包括肿瘤固有过程，如上皮去分化和上皮向间质转化，以及肿瘤微环境因素，如T细胞介导的免疫和癌症相关成纤维细胞活性。出乎意料的是，lnm相关基因几乎普遍与恶性细胞中的上皮去分化相关。与LNM负相关的基因包括在分化良好的恶性细胞中表达的鳞状上皮分化调节因子，而与LNM正相关的基因则代表通常被p53-DREAM通路抑制的细胞周期调节因子。这些前lnm基因在TP53突变和HPV + ve HNCs的增殖恶性细胞中过表达，并且与干细胞密切相关，表明它们代表了转移前癌症干细胞样细胞的标志物。lnm相关基因在高级别口腔癌前病变中不受调控，在原发性HNCs中随着肿瘤级别的提高而进一步不受调控，在淋巴结转移中进一步不受调控。在HNC中，患者的生存受到多种生物学过程的影响，并受到肿瘤免疫和基质微环境的强烈影响。相反，LNM似乎主要是由恶性细胞可塑性驱动的，其特征是上皮去分化加上emt独立的增殖和干性。我们的研究结果假设LNM最初是由p53- dream介导的细胞周期基因抑制在早期肿瘤发生过程中丢失引起的。在线版本包含补充材料，可在10.1186/s13073-023-01236-w获得。
The prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data. We performed meta-analysis across 29 gene expression studies including 2074 primary HNC biopsies to identify genes and transcriptional pathways associated with survival and lymph node metastasis (LNM). To understand the biological roles of these genes in HNC, we identified their associated cancer pathways, as well as the cell types that express them within HNC tumor microenvironments, by integrating single-cell RNA-seq and bulk RNA-seq from sorted cell populations. Patient survival-associated genes were heterogenous and included drivers of diverse tumor biological processes: these included tumor-intrinsic processes such as epithelial dedifferentiation and epithelial to mesenchymal transition, as well as tumor microenvironmental factors such as T cell-mediated immunity and cancer-associated fibroblast activity. Unexpectedly, LNM-associated genes were almost universally associated with epithelial dedifferentiation within malignant cells. Genes negatively associated with LNM consisted of regulators of squamous epithelial differentiation that are expressed within well-differentiated malignant cells, while those positively associated with LNM represented cell cycle regulators that are normally repressed by the p53-DREAM pathway. These pro-LNM genes are overexpressed in proliferating malignant cells of TP53 mutated and HPV + ve HNCs and are strongly associated with stemness, suggesting that they represent markers of pre-metastatic cancer stem-like cells. LNM-associated genes are deregulated in high-grade oral precancerous lesions, and deregulated further in primary HNCs with advancing tumor grade and deregulated further still in lymph node metastases. In HNC, patient survival is affected by multiple biological processes and is strongly influenced by the tumor immune and stromal microenvironments. In contrast, LNM appears to be driven primarily by malignant cell plasticity, characterized by epithelial dedifferentiation coupled with EMT-independent proliferation and stemness. Our findings postulate that LNM is initially caused by loss of p53-DREAM-mediated repression of cell cycle genes during early tumorigenesis. The online version contains supplementary material available at 10.1186/s13073-023-01236-w.
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DOI：
10.1016/j.trsl.2012.02.002
发表时间：
2012-09
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Wise-Draper TM;Draper DJ;Gutkind JS;Molinolo AA;Wikenheiser-Brokamp KA;Wells SI
通讯作者：
Wells SI
影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
全基因组表达和拷贝数分析标识了牙龈癌中的驱动基因。
影响因子：
3.7
作者：
Ambatipudi, Srikant;Gerstung, Moritz;Pandey, Manishkumar;Samant, Tanuja;Patil, Asawari;Kane, Shubhada;Desai, Rajiv S.;Schaeffer, Alejandro A.;Beerenwinkel, Niko;Mahimkar, Manoj B.
通讯作者：
Mahimkar, Manoj B.
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
5
作者：
Bhosale PG;Cristea S;Ambatipudi S;Desai RS;Kumar R;Patil A;Kane S;Borges AM;Schäffer AA;Beerenwinkel N;Mahimkar MB
通讯作者：
Mahimkar MB