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

Abstract

Summary 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.

FGFR1 Oncogenic Activation Reveals an Alternative Cell of Origin of SCLC in Rb1/p53 Mice

“…profile to SCLC and ALs. The expression profile of ALs has been described recently for cisplatin-treated Ad5-CMV-Cre-injected RPM (Rb1/Trp53/Mycl) mice (Bö ttger et al, 2019). For consistency, we isolated BLs from RPM mice and compared their expression profile with that of either ALs or SCLC of RPM mice.…”

Recent progress in mapping the emerging landscape of the small-cell lung cancer genome

“…In addition, these studies consistently showed that NFIB overexpression increased cell viability and proliferation during transformation and that suppression of NFIB expression in cell lines inhibited cell proliferation and activated cell death. However, although this NFIB-driven transcription program promotes tumor growth and metastasis, it confers cisplatin sensitivity to tumors that are otherwise refractory to chemotherapy 105 . These findings strongly suggest that increased transcriptional activity of NFIB is a key driver of SCLC development and malignant progression but may introduce a vulnerability to be exploited for therapeutic intervention.…”

Axon-like protrusions promote small cell lung cancer migration and metastasis

“…Higher levels of the neuronal markers such as NSE (neuron-specific enolase) correlate with shorter survival and more metastatic disease in SCLC patients (Carney et al, 1982; van Zandwijk et al, 1992; Dong et al, 2019). Broad neuronal gene expression programs are enriched in metastases from mouse models of SCLC, however, whether SCLC cells actually gain neuronal characteristics and whether neuronal features are key regulators of metastatic ability has not been previously characterized (Denny et al, 2016; Wu et al, 2016; Yang et al, 2018; Böttger et al, 2019).…”