Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma.
Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma.
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DOI：
10.1038/s42003-023-05668-3
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发表时间：
2023-12-21
影响因子：
5.9
通讯作者：
De, Subhajyoti
中科院分区：
文献类型：
--
作者：
Biswas, Antara;Sahoo, Sarthak;Riedlinger, Gregory M.;Ghodoussipour, Saum;Jolly, Mohit K.;De, Subhajyoti
肿瘤内的异质性是导致尿路上皮性膀胱癌(UBC)治疗失败和生存率低的原因之一。从UBC队列中分析转录组，我们报告了肿瘤内转录异质性表明肿瘤细胞在上皮样和间充质样转录状态下共存，并且它们之间发生双向转换，发生在肿瘤亚克隆内和之间。我们模拟了细胞系中这些部分可遗传状态之间的自发和可逆转变，并描述了它们的种群动力学。SMAD3、KLF4和PPARG是转录动力学的关键调控标记。营养限制，就像在大肿瘤的核心，放射治疗扰乱了动态，最初选择了暂时耐药的表型，然后重建了异质性和生长潜力，推动了适应性进化。PPARG低表达的转录状态占优势表明UBC患者具有侵袭性表型。我们认为，表型可塑性和动态的、非遗传的肿瘤内异质性调节了疾病进展的轨迹和UBC的适应性治疗反应。一组功能基因组学和统计分析确定并建立了肿瘤生长和正在治疗的尿路上皮性膀胱癌转录状态动态和可塑性的关键决定因素。
Intra-tumor heterogeneity contributes to treatment failure and poor survival in urothelial bladder carcinoma (UBC). Analyzing transcriptome from a UBC cohort, we report that intra-tumor transcriptomic heterogeneity indicates co-existence of tumor cells in epithelial and mesenchymal-like transcriptional states and bi-directional transition between them occurs within and between tumor subclones. We model spontaneous and reversible transition between these partially heritable states in cell lines and characterize their population dynamics. SMAD3, KLF4 and PPARG emerge as key regulatory markers of the transcriptional dynamics. Nutrient limitation, as in the core of large tumors, and radiation treatment perturb the dynamics, initially selecting for a transiently resistant phenotype and then reconstituting heterogeneity and growth potential, driving adaptive evolution. Dominance of transcriptional states with low PPARG expression indicates an aggressive phenotype in UBC patients. We propose that phenotypic plasticity and dynamic, non-genetic intra-tumor heterogeneity modulate both the trajectory of disease progression and adaptive treatment response in UBC. A set of functional genomics and statistical analyses identifies and establishes key determinants of transcriptional state dynamics and plasticity during tumor growth and under treatment in urothelial bladder carcinoma.
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影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
单细胞 RNA 测序强调了炎性癌症相关成纤维细胞在膀胱尿路上皮癌中的作用。
影响因子：
16.6
作者：
Chen Z;Zhou L;Liu L;Hou Y;Xiong M;Yang Y;Hu J;Chen K
通讯作者：
Chen K
影响因子：
9
作者：
Adjuto-Saccone M;Soubeyran P;Garcia J;Audebert S;Camoin L;Rubis M;Roques J;Binétruy B;Iovanna JL;Tournaire R
通讯作者：
Tournaire R
影响因子：
7
作者：
Barkley D;Rao A;Pour M;França GS;Yanai I
通讯作者：
Yanai I
DOI：
10.15252/embj.2021108647
发表时间：
2021-09-15
期刊：
The EMBO journal
影响因子：
--
作者：
Brabletz S;Schuhwerk H;Brabletz T;Stemmler MP
通讯作者：
Stemmler MP