Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer

被引：52

作者：

Bottger, Franziska ^{[4
]}

Semenova, Ekaterina A. ^{[1
,2
]}

Song, Ji-Ying ^{[3
]}

Ferone, Giustina ^{[1
,2
]}

van der Vliet, Jan ^{[1
,2
]}

Cozijnsen, Miranda ^{[1
,2
]}

Bhaskaran, Rajith ^{[1
,2
]}

Bombardelli, Lorenzo ^{[1
,2
]}

Piersma, Sander R. ^{[4
]}

Pham, Thang, V ^{[4
]}

Jimenez, Connie R. ^{[4
]}

Berns, Anton ^{[1
,2
]}

机构：

[1] Netherlands Canc Inst, Oncode Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands

[2] Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands

[3] Netherlands Canc Inst, Dept Anim Pathol, NL-1066 CX Amsterdam, Netherlands

[4] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam UMC, NL-1081 HV Amsterdam, Netherlands

来源：

CELL REPORTS | 2019年 / 27卷 / 11期

基金：

欧洲研究理事会;

关键词：

THERAPY RESISTANCE; CARCINOMA; INACTIVATION; PROGRESSION; NETWORKS; DISEASE; ORIGIN; DRIVER; TRP53; NFIB;

D O I：

10.1016/j.celrep.2019.05.057

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Small-cell lung cancer is the most aggressive type of lung cancer, characterized by a remarkable response to chemotherapy followed by development of resistance. Here, we describe SCLC subtypes in Mycl-and Nfib-driven GEMM that include CDH1-high peripheral primary tumor lesions and CDH1 -negative, aggressive intrapulmonary metastases. Cisplatin treatment preferentially eliminates the latter, thus revealing a striking differential response. Using a combined transcriptomic and proteomic approach, we find a marked reduction in proliferation and metabolic rewiring following cisplatin treatment and present evidence for a distinctive metabolic and structural profile defining intrinsically resistant populations. This offers perspectives for effective combination therapies that might also hold promise for treating human SCLC, given the very similar response of both mouse and human SCLC to cisplatin.

引用

页码：3345 / +

页数：18

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