Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population.
Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population.
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DOI：
10.1038/s41598-021-94941-8
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发表时间：
2021-07-29
影响因子：
4.6
通讯作者：
Mitchell A
中科院分区：
文献类型：
--
作者：
Khoshkenar P;Lowry E;Mitchell A
肿瘤内的癌细胞表现出高度的表型变异性。这种可变性被认为允许一些细胞在看似有效的药物治疗后存活并持续存在。vemurafenib是一种针对黑色素瘤中常见的致癌BRAF突变的信号抑制剂，其研究表明，通过长期增殖测量的耐药细胞间变异源于治疗前基因表达的表观遗传差异。然而，目前尚不清楚被抑制的BRAF下游信号的再激活是否在细胞间具有异质性，而这被认为是耐药性的关键步骤。虽然先前的研究证实，信号再激活发生在治疗后数小时至数天，但他们采用的是不适合检测细胞间异质性的批量检测来监测再激活。我们假设信号再激活是异质的，并且对于一小部分耐药细胞几乎是瞬时的。我们通过在单细胞分辨率下监测信号动力学来测试这一假设，并观察到尽管高度一致的初始抑制，大约15%的细胞在治疗一小时内重新激活信号。此外，通过在多天内跟踪细胞系，我们确定这些细胞确实比邻近细胞增殖更多，从而确定快速信号再激活可以预测长期的vemurafenib耐药性。
Cancer cells within tumors display a high degree of phenotypic variability. This variability is thought to allow some of the cells to survive and persist after seemingly effective drug treatments. Studies on vemurafenib, a signaling inhibitor that targets an oncogenic BRAF mutation common in melanoma, suggested that cell-to-cell variation in drug resistance, measured by long-term proliferation, originates from epigenetic differences in gene expression that pre-exist treatment. However, it is still unknown whether reactivation of signaling downstream to the inhibited BRAF, thought to be a key step for resistance, is heterogeneous across cells. While previous studies established that signaling reactivation takes place many hours to days after treatment, they monitored reactivation with bulk-population assays unsuitable for detecting cell-to-cell heterogeneity. We hypothesized that signaling reactivation is heterogeneous and is almost instantaneous for a small subpopulation of resistant cells. We tested this hypothesis by monitoring signaling dynamics at a single-cell resolution and observed that despite highly uniform initial inhibition, roughly 15% of cells reactivated signaling within an hour of treatment. Moreover, by tracking cell lineages over multiple days, we established that these cells indeed proliferated more than neighboring cells, thus establishing that rapid signaling reactivation predicts long-term vemurafenib resistance.
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影响因子：
64.5
作者：
Regot S;Hughey JJ;Bajar BT;Carrasco S;Covert MW
通讯作者：
Covert MW
肺癌演化过程中高塑性细胞状态的出现。
影响因子：
50.3
作者：
Marjanovic ND;Hofree M;Chan JE;Canner D;Wu K;Trakala M;Hartmann GG;Smith OC;Kim JY;Evans KV;Hudson A;Ashenberg O;Porter CBM;Bejnood A;Subramanian A;Pitter K;Yan Y;Delorey T;Phillips DR;Shah N;Chaudhary O;Tsankov A;Hollmann T;Rekhtman N;Massion PP;Poirier JT;Mazutis L;Li R;Lee JH;Amon A;Rudin CM;Jacks T;Regev A;Tammela T
通讯作者：
Tammela T
振荡应激刺激揭示了酵母 MAPK 信号网络的致命弱点。
DOI：
10.1126/science.aab0892
发表时间：
2015-12-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mitchell A;Wei P;Lim WA
通讯作者：
Lim WA
影响因子：
50.3
作者：
LaFave LM;Kartha VK;Ma S;Meli K;Del Priore I;Lareau C;Naranjo S;Westcott PMK;Duarte FM;Sankar V;Chiang Z;Brack A;Law T;Hauck H;Okimoto A;Regev A;Buenrostro JD;Jacks T
通讯作者：
Jacks T
影响因子：
64.8
作者：
Shaffer SM;Dunagin MC;Torborg SR;Torre EA;Emert B;Krepler C;Beqiri M;Sproesser K;Brafford PA;Xiao M;Eggan E;Anastopoulos IN;Vargas-Garcia CA;Singh A;Nathanson KL;Herlyn M;Raj A
通讯作者：
Raj A