KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.
KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.
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DOI：
10.1038/s41586-023-06324-w
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发表时间：
2023-07
期刊：
影响因子：
64.8
通讯作者：
Desai, Tushar J.
中科院分区：
文献类型：
--
作者：
Juul, Nicholas H.;Yoon, Jung-Ki;Martinez, Marina C.;Rishi, Neha;Kazadaeva, Yana I.;Morri, Maurizio;Neff, Norma F.;Trope, Winston L.;Shrager, Joseph B.;Sinha, Rahul;Desai, Tushar J.
许多癌症起源于被驱动复制的体细胞突变劫持的干细胞或祖细胞，例如肺泡II型（AT 2）细胞的快速腺瘤性转化。在这里，我们展示了一个不同的场景：KrasG12D在完全分化的AT1细胞中的表达将它们缓慢而异步地重新编程回AT2细胞，然后产生惰性肿瘤。与人的鳞腺癌一样，肿瘤细胞以非破坏性的方式沿沿着完整的肺泡壁缓慢扩散，并且具有低ERK活性。我们发现，AT1和AT2细胞作为不同的起源细胞，并表现出不同的反应，伴随Wnt激活和KrasG12D诱导，这大大增加了AT2衍生的，但抑制AT1衍生的腺瘤增殖。在KrasG12D诱导的AT1细胞中，ERK活性的药理学增强显著增加了转化效率、增殖和从纯麻风向混合肿瘤组织学进展的可能性。总的来说，我们已经确定了一种新的细胞来源的肺腺癌，AT1细胞，它概括了人类麻风癌的特点。在这样做的过程中，我们还发现了致癌Kras在腺瘤转化的过程中将分化和静止细胞重编程回其亲本干细胞的能力。我们的工作进一步揭示了，无论给定癌症的当前分子谱和驱动癌基因如何，起源细胞对其随后的行为产生了普遍和持久的影响。致癌性Kras将分化的AT1细胞重编程为AT2细胞，其产生与人类鳞片状肺腺癌共有特征的惰性和功能受限的肿瘤。
Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by rapid adenomatous transformation of pulmonary alveolar type II (AT2) cells. Here, we demonstrate a different scenario: expression of KrasG12D in fully differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 cells that go on to generate indolent tumors. Like human lepidic adenocarcinoma, the tumor cells slowly spread along intact alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant Wnt activation and KrasG12D induction, which dramatically increases AT2-derived but inhibits AT1-derived adenoma proliferation. Pharmacological augmentation of ERK activity in KrasG12D-induced AT1 cells dramatically increases transformation efficiency, proliferation, and likelihood of progression from pure lepidic to mixed tumor histology. Overall, we have identified a novel cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic Kras to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer’s current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behavior. Oncogenic Kras reprograms differentiated AT1 cells into AT2 cells that generate indolent and functionally constrained tumors that share features with human lepidic lung adenocarcinoma.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
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
DOI：
10.1016/j.jtho.2020.08.005
发表时间：
2020-12
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Caso R;Sanchez-Vega F;Tan KS;Mastrogiacomo B;Zhou J;Jones GD;Nguyen B;Schultz N;Connolly JG;Brandt WS;Bott MJ;Rocco G;Molena D;Isbell JM;Liu Y;Mayo MW;Adusumilli PS;Travis WD;Jones DR
通讯作者：
Jones DR
影响因子：
3.6
作者：
Berry, Mark F.;Gao, Rebecca;Shrager, Joseph
通讯作者：
Shrager, Joseph
影响因子：
3.7
作者：
Lin C;Song H;Huang C;Yao E;Gacayan R;Xu SM;Chuang PT
通讯作者：
Chuang PT