Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach.
Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach.
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DOI：
10.3390/cancers12123678
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发表时间：
2020-12-08
期刊：
影响因子：
5.2
通讯作者：
Saganti PB
中科院分区：
文献类型：
--
作者：
Iacobas DA;Mgbemena VE;Iacobas S;Menezes KM;Wang H;Saganti PB
我们将个性化基因治疗的基因组结构原理应用于一例透明细胞肾细胞癌（ccRCC）病例。尽管进行了数十年的研究，但寻找这种疾病的分子机制，更重要的是，治疗方案的过程仍然是一项正在进行的工作。我们分析了Fuhrman 3级转移性ccRCC患者手术切除的右肾中的胸壁转移、两个不同的癌结节和无癌周围组织的转录组。这些研究表明，即使是来自同一肾脏的组织病理学上同等分类的癌症结节也具有不同的转录组拓扑结构，不仅需要为每位患者，甚至需要为每个癌症结节量身定制治疗方案。我们鉴定了死亡相关蛋白激酶3（DAPK 3）、转录激活抑制因子（TASOR）、具有序列相似性27的家族成员C、长非编码RNA（FAM 27 C）、和UDP-N-乙酰葡糖胺基转移酶亚基（ALG 13）作为四个轮廓区域的基因主调节因子，并提出了TASOR和ALG 13的表达操纵可以选择性地破坏癌细胞而不破坏癌细胞的分子机制。影响许多正常细胞。从基因组结构范例（GFP）的角度分析了手术切除的转移性透明细胞肾细胞癌样本的已发表转录组数据，以确定基因治疗的最佳靶点。GFP认为转录组是一个多维的数学对象，受一组动态的表达控制和基因之间的相关性的约束。胸壁转移瘤、两个不同的癌结节和右肾周围正常组织中的每个基因通过三个独立的测量来表征：平均表达水平、相对表达变化和与其他基因的表达相关性。这些分析确定了癌症诱导的趋化因子和血管内皮生长因子（VEGF）信号传导、细胞凋亡、基础转录因子、细胞周期、氧化磷酸化、肾细胞癌和RNA聚合酶途径的调节、控制和重塑。有趣的是，这三个癌症区域表现出不同的转录组学组织，这表明基因治疗不应该只针对每一个患者，也应该针对每一个主要的癌症结节。在基因制高点的基础上建立了基因层次结构，并在每个区域鉴定了基因主调控因子DAPK 3、TASOR、FAM 27 C和ALG 13。我们描述了TASOR过表达和ALG 13沉默选择性影响癌细胞而对正常细胞影响很小的分子机制。
We applied the genomic fabric principles for personalized gene therapy to a case of clear cell renal cell carcinoma (ccRCC). Despite decades of research, the process of finding the molecular mechanisms responsible for the disease and, more importantly, the therapeutic solution is still a work in progress. We analyzed the transcriptomes of the chest wall metastasis, two distinct cancer nodules, and the cancer-free surrounding tissue in the surgically removed right kidney of a Fuhrman grade 3 metastatic ccRCC patient. The studies revealed that even histopathologically equally classified cancer nodules from the same kidney have different transcriptomic topologies, requiring tailored therapeutic solutions not only for each patient but even for each cancer nodule. We identified death-associated protein kinase 3 (DAPK3); transcription activation suppressor (TASOR); family with sequence similarity 27, member C, long non-coding RNA (FAM27C); and UDP-N-acetylglucosaminyltransferase subunit (ALG13) as the gene master regulators of the four profiled regions and proposed molecular mechanisms by which expression manipulation of TASOR and ALG13 may selectively destroy the cancer cells without affecting many of the normal cells. Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma samples were analyzed from the genomic fabric paradigm (GFP) perspective to identify the best targets for gene therapy. GFP considers the transcriptome as a multi-dimensional mathematical object constrained by a dynamic set of expression controls and correlations among genes. Every gene in the chest wall metastasis, two distinct cancer nodules, and the surrounding normal tissue of the right kidney was characterized by three independent measures: average expression level, relative expression variation, and expression correlation with each other gene. The analyses determined the cancer-induced regulation, control, and remodeling of the chemokine and vascular endothelial growth factor (VEGF) signaling, apoptosis, basal transcription factors, cell cycle, oxidative phosphorylation, renal cell carcinoma, and RNA polymerase pathways. Interestingly, the three cancer regions exhibited different transcriptomic organization, suggesting that the gene therapy should not be personalized only for every patient but also for each major cancer nodule. The gene hierarchy was established on the basis of gene commanding height, and the gene master regulators DAPK3, TASOR, FAM27C and ALG13 were identified in each profiled region. We delineated the molecular mechanisms by which TASOR overexpression and ALG13 silencing would selectively affect the cancer cells with little consequences for the normal cells.
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DOI：
10.1158/1078-0432.ccr-18-0269
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Damayanti NP;Budka JA;Khella HWZ;Ferris MW;Ku SY;Kauffman E;Wood AC;Ahmed K;Chintala VN;Adelaiye-Ogala R;Elbanna M;Orillion A;Chintala S;Kao C;Linehan WM;Yousef GM;Hollenhorst PC;Pili R
通讯作者：
Pili R
磁共振成像放射分析分析用于预测清晰细胞肾细胞癌中高级组织学和坏死的预测：初步经验。
影响因子：
3.2
作者：
Dwivedi DK;Xi Y;Kapur P;Madhuranthakam AJ;Lewis MA;Udayakumar D;Rasmussen R;Yuan Q;Bagrodia A;Margulis V;Fulkerson M;Brugarolas J;Cadeddu JA;Pedrosa I
通讯作者：
Pedrosa I
影响因子：
16.6
作者：
Douse CH;Tchasovnikarova IA;Timms RT;Protasio AV;Seczynska M;Prigozhin DM;Albecka A;Wagstaff J;Williamson JC;Freund SMV;Lehner PJ;Modis Y
通讯作者：
Modis Y
影响因子：
3.7
作者：
Gresakova, Veronika;Novosadova, Vendula;Sedlacek, Radislav
通讯作者：
Sedlacek, Radislav
肾癌干细胞的生物标志物发现。
DOI：
10.1002/cjp2.91
发表时间：
2018-01
期刊：
The journal of pathology. Clinical research
影响因子：
--
作者：
Corrò C;Moch H
通讯作者：
Moch H