Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Bottger F

PROVIDER: S-EPMC6581744 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Böttger Franziska F Semenova Ekaterina A EA Song Ji-Ying JY Ferone Giustina G van der Vliet Jan J Cozijnsen Miranda M Bhaskaran Rajith R Bombardelli Lorenzo L Piersma Sander R SR Pham Thang V TV Jimenez Connie R CR Berns Anton A

Cell reports 20190601 11

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, w ...[more]

PMID: 31189116

Similar Datasets

Project description:Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure