Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

Semenova, Ekaterina A.; Kwon, Min-Chul; Monkhorst, Kim; Song, Ji‐Ying; Bhaskaran, Rajith; Krijgsman, Oscar; Kuilman, Thomas; Peters, Dennis; Buikhuisen, Wieneke A.; Smit, Egbert F.; Pritchard, Colin E.J.; Cozijnsen, Miranda; Vliet, Jan van der; Zevenhoven, John; Lambooij, Jan-Paul; Proost, Natalie; Montfort, Erwin van; Velds, Arno; Huijbers, Ivo J.; Berns, Anton

doi:10.1016/j.celrep.2016.06.020

Cited by 122 publications

(144 citation statements)

References 43 publications

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“…Brain-specific deletion of both Nfi genes using conditional knockout alleles may overcome some of these issues, assuming that double homozygous knockout in the brain has no effect on viability. In theory, utilising the recent generation of a conditional Nfib overexpression model (Semenova et al, 2016) crossed to an Nfia knockout mouse would be able to demonstrate whether increasing NFIB protein levels could compensate for the absence of Nfia. However, this would require ectopic NFIB expression to mimic both the expression level and temporal and spatial specificity of NFIA.…”

Section: Discussionmentioning

confidence: 99%

Combined allelic dosage of Nfia and Nfib regulates cortical development

Bunt

Osinski

Lim

et al. 2017

Brain and Neuroscience Advances

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Background: Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate similar biological processes, as their expression patterns, regulation of target genes and individual knockout phenotypes overlap. We hypothesised that the combined allelic loss of Nfia and Nfib would culminate in more severe defects in the cerebral cortex than loss of a single member. Methods: We combined immunofluorescence, co-immunoprecipitation, gene expression analysis and immunohistochemistry on knockout mouse models to investigate whether nuclear factor I A and nuclear factor I B function similarly and whether increasing allelic loss of Nfia and Nfib caused a more severe phenotype. Results: We determined that the biological functions of nuclear factor I A and nuclear factor I B overlap during early cortical development. These proteins are co-expressed and can form heterodimers in vivo. Differentially regulated genes that are shared between Nfia and Nfib knockout mice are highly enriched for nuclear factor I binding sites in their promoters and are associated with neurodevelopment. We found that compound heterozygous deletion of both genes resulted in a cortical phenotype similar to that of single homozygous Nfia or Nfib knockout embryos. This was characterised by retention of the interhemispheric fissure, dysgenesis of the corpus callosum and a malformed dentate gyrus. Double homozygous knockout of Nfia and Nfib resulted in a more severe phenotype, with increased ventricular enlargement and decreased numbers of differentiated glia and neurons. Conclusion: In the developing cerebral cortex, nuclear factor I A and nuclear factor I B share similar biological functions and function additively, as the combined allelic loss of these genes directly correlates with the severity of the developmental brain phenotype.

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Section: Discussionmentioning

confidence: 99%

Combined allelic dosage of Nfia and Nfib regulates cortical development

Bunt

Osinski

Lim

et al. 2017

Brain and Neuroscience Advances

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“…The addition of fluorescent reporters whose expression is turned on by the Cre recombinase in these mutant mice helps in tracking and purifying cancer cells as they grow from small lesions to fully metastatic tumors (21). Similarly, Cre-inducible expression of luciferase can be incorporated to monitor and quantify tumor development in situ (14,22).…”

Section: Autochthonous Gemms Of Sclcmentioning

confidence: 99%

“…However, GEMMs remain a key system in which to study the mechanisms of metastatic progression. Recently, three studies have highlighted a major role for the Nfib transcription factor in the metastatic progression of SCLC (14,15,21) ( Figure 2). The Nfib gene is frequently amplified in mouse tumors as they become metastatic (21,67); in human tumors NFIB is more rarely amplified (12,59,60) but high expression is found in over 50% of metastases.…”

Section: Metastatic Sclcmentioning

confidence: 99%

“…This is possibly due to the still limited number of samples that have been analyzed in depth. Moreover, with the exception of Notch signaling (12), two Myc family members (c-Myc and L-Myc) (14), and Pten (18,20), very few of these recurrent alterations have been functionally tested in GEMMs or even PDX models. Thus, it is difficult to know if these genetic alterations represent distinct subtypes of SCLC that may have different growth properties or may respond to various therapies differently.…”

Section: Genomic Studies Of Human Sclc and Genetic Diversitymentioning

confidence: 99%

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Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Shue¹,

Lim²,

Sage³

2018

Transl. Lung Cancer Res.

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Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in Abstract: Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth.We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents.A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

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“…Semenova et al's work identifying the transcription factor NFIB as a driver of progression helps to better understand the mechanism of tumor progression and acquired resistance to chemotherapy (12). By using an inactivation of TP53 and Rb1 for a mouse model of SCLC, they overcame the first struggle with SCLC: paucity of tissue samples available for investigation.…”

mentioning

confidence: 99%