Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Denny, Sarah K.; Yang, Dian; Chuang, Chen Hua; Brady, Jennifer J.; Lim, Jing Shan; Grüner, Barbara M.; Chiou, Shin Heng; Schep, Alicia N.; Baral, Jessika; Hamard, Cécile; Antoine, Martine; Wislez, Marie; Kong, Christina S.; Connolly, Andrew J.; Park, Kwon Sik; Sage, Julien; Greenleaf, William J.; Winslow, Monte M.

doi:10.1016/j.cell.2016.05.052

Cited by 323 publications

(404 citation statements)

References 52 publications

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“…It is also noteworthy, however, that it has been difficult to grow SCLC allografts or xenografts orthotopically [e.g., (23)] whereas tumors rapidly expanded outside the lungs, thus PDX studies are performed in a different microenvironment than the lungs. Tail vein injection of SCLC cells leads to the growth of tumors in the liver, which can provide a model for SCLC metastasis to the liver (21). A truly exciting development in the field has been the observation that SCLC patients often have more CTCs than what is found in other cancer types.…”

Section: Allograft and Xenograft Modelsmentioning

confidence: 99%

“…With recent advances in genome engineering, including CRISPR/Cas9, it is likely that additional models will be soon available to the community. 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%

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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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Section: Allograft and Xenograft Modelsmentioning

confidence: 99%

Section: Autochthonous Gemms Of Sclcmentioning

confidence: 99%

Section: Metastatic Sclcmentioning

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.

Self Cite

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“…2011) and it promotes metastasis through widespread increase in chromatin accessibility (Denny et al. 2016), suggesting it plays a critical role in cancer development (Becker‐Santos et al. 2017).…”

Section: Introductionmentioning

confidence: 99%

Nfib hemizygous mice are protected from hyperoxic lung injury and death

et al. 2017

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Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild‐type (Wt) littermates were exposed to 100% O2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real‐time PCR. Unexpectedly, Nfib hemizygous mice (0/14–0%) had significantly lower mortality compared to Wt mice (10/22–45%) at 80 h of hyperoxia (P < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP‐2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild‐type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild‐type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development.

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“…Without pioneer TFs to open the chromatin structure at cell proliferation genes, mitogenic stimuli may not be able to reach their full potential in promoting cell cycle activation in the adult heart (Denny et al, 2016). Therefore, it will be important in the future to determine whether these TFs…”

Section: Discussionmentioning

confidence: 99%

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

Sim

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Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Cited by 323 publications

References 52 publications

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

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

Nfib hemizygous mice are protected from hyperoxic lung injury and death

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

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