Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor.
Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor.
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癌细胞进入适应性的持久性，可在放射疗法中生存并重新填充肿瘤。
DOI：
10.1002/advs.202204177
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发表时间：
2023-03
期刊：
影响因子：
--
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残留肿瘤细胞的重新聚集阻碍了根治性放射治疗，但其机制尚不完全清楚。最近人们认识到，癌细胞采用短暂的持久性来在化疗或靶向治疗的压力下生存，并促进最终的复发。在这里，它表明，癌细胞同样进入“辐射耐受持久”(RTP)状态，以躲避辐射压力在体外和体内。RTP细胞的特点是细胞体积增大，核型复杂，激活的I型干扰素途径和以CST3和SNCG为代表的两种基因模式。RTP细胞有可能通过病毒萌芽样分裂再生后代，而I型干扰素介导的抗病毒信号会损害后代的产生。去除CST3或SNCG不会减少RTP细胞的形成，但可以抑制RTP细胞的萌发，并损害肿瘤的再繁殖。有趣的是，RTP细胞产生的子代细胞会主动丢失其异常的染色体片段，并逐渐恢复到与其未受辐射的亲代细胞相似的染色体结构。综上所述，本研究揭示了肿瘤再繁殖的一种新机制，即癌细胞群体通过多倍化和去多倍化来实现可逆的辐射持续性，从而在放疗后存活并重新填充肿瘤，为改善接受放射治疗的患者的预后提供了新的治疗理念。癌细胞通过多倍化进入辐射耐受性(RTP)状态以在辐射中生存。然后，RTP细胞解多倍化，通过病毒萌芽样分裂产生类似亲代的后代，恢复肿瘤再繁殖。RNA转录产物(SMART)5‘端的10倍和开关机制揭示了I型干扰素和两个基因面板在萌发表型中的重要作用，为放射治疗提供了新的治疗策略。
Repopulation of residual tumor cells impedes curative radiotherapy, yet the mechanism is not fully understood. It is recently appreciated that cancer cells adopt a transient persistence to survive the stress of chemo‐ or targeted therapy and facilitate eventual relapse. Here, it is shown that cancer cells likewise enter a “radiation‐tolerant persister” (RTP) state to evade radiation pressure in vitro and in vivo. RTP cells are characterized by enlarged cell size with complex karyotype, activated type I interferon pathway and two gene patterns represented by CST3 and SNCG. RTP cells have the potential to regenerate progenies via viral budding‐like division, and type I interferon‐mediated antiviral signaling impaired progeny production. Depleting CST3 or SNCG does not attenuate the formation of RTP cells, but can suppress RTP cells budding with impaired tumor repopulation. Interestingly, progeny cells produced by RTP cells actively lose their aberrant chromosomal fragments and gradually recover back to a chromosomal constitution similar to their unirradiated parental cells. Collectively, this study reveals a novel mechanism of tumor repopulation, i.e., cancer cell populations employ a reversible radiation‐persistence by poly‐ and de‐polyploidization to survive radiotherapy and repopulate the tumor, providing a new therapeutic concept to improve outcome of patients receiving radiotherapy. Cancer cells enter a radiation‐tolerant persister (RTP) state by polyploidization to survive radiation. RTP cells then de‐polyploidize and generate parent‐like progenies via viral budding‐like division resuming tumor repopulation. 10× and switching mechanism at 5′ end of the RNA transcript (SMART) single cell RNA‐seq unveil the essential role of type I interferon and two gene panels in budding phenotype, pointing to novel therapeutic strategies in radiotherapy.
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影响因子：
50.3
作者：
Guler, Gulfem Dilek;Tindell, Charles Albert;Classon, Marie
通讯作者：
Classon, Marie
影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex
DOI：
10.1002/path.5051
发表时间：
2018-05
期刊：
The Journal of pathology
影响因子：
--
作者：
Alderdice M;Richman SD;Gollins S;Stewart JP;Hurt C;Adams R;McCorry AM;Roddy AC;Vimalachandran D;Isella C;Medico E;Maughan T;McArt DG;Lawler M;Dunne PD
通讯作者：
Dunne PD
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
28.2
作者：
Duy C;Li M;Teater M;Meydan C;Garrett-Bakelman FE;Lee TC;Chin CR;Durmaz C;Kawabata KC;Dhimolea E;Mitsiades CS;Doehner H;D'Andrea RJ;Becker MW;Paietta EM;Mason CE;Carroll M;Melnick AM
通讯作者：
Melnick AM