Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma

Sutherland, Kate D.; Song, Ji‐Ying; Kwon, Min-Chul; Proost, Natalie; Zevenhoven, John; Berns, Anton

doi:10.1073/pnas.1319963111

Cited by 209 publications

(236 citation statements)

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“…To test the effect of Klf4 deletion on other cell types, we stained the lung tissues with antibodies to AT1 cell marker reported that AT2 cells are the predominant cells of origin of adenocarcinoma that is driven by K-ras activation. [21][22][23]31,34 Our results suggest that Klf4 deletion could be a driving force of lung tumorigenesis through stimulating AT2 cells in mouse lung.…”

Section: Resultsmentioning

confidence: 67%

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KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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Section: Resultsmentioning

confidence: 67%

“…Both AT2 cells and Clara cells had the ability to initiate malignant transformation, but the initiating cell type influences the type of tumors that arose. 23 These findings suggest that AT2 cells are the major origin of lung tumorigenesis.…”

mentioning

confidence: 90%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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“…However, comprehensive studies that target diverse genomic alterations to a greater array of defined cell types are simply not feasible using current transgene-based systems. The use of adenoviral vectors with cell type-specific promoters has greatly accelerated the investigation of the cell of origin of lung adenocarcinoma and small cell lung cancer (Sutherland et al 2011(Sutherland et al , 2014, suggesting that similar approaches could rapidly advance our understanding of the precise cell type-genotype combinations that can give rise to PDAC. Soft tissue sarcomas can be generated in Kras LSL-G12D ; p53 f/f mice by viral-Cre infection of cells within the muscle (Kirsch et al 2007); therefore, we initially suspected that this would be a major impediment for generating viral-induced PDAC models.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

et al. 2015

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Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.

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“…According to our results, the generation of 'acquired' CSCs (induced by EMT) at least needs some particular heredity alterations. In fact, genetic heterogeneity was already found to exist in lung CSC populations, and related to intrinsical cellular diversity (53,54). Notably, Kreso et al proposed their own hypothesis regarding genetic alteration and CSC (two mutually exclusive models for tumor hererogeneity) (55).…”

Section: Discussionmentioning

confidence: 99%

SNAILs promote G1 phase in selected cancer cells

Xue

Zhou

et al. 2015

Int J Oncol

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Abstract. Cells can acquire a stem-like cell phenotype through epithelial-mesenchymal transition (EMT). However, it is not known which of the stem-like cancer cells are generated by these phenotype transitions. We studied the EMT-inducing roles of SNAILs (the key inducers for the onset of EMT) in selected cancer cells (lung cancer cell line with relatively stable genome), in order to provide more implications for the investigation of EMT-related phenotype transitions in cancer. However, SNAILs fail to induce completed EMT. In addition, we proved that Snail accelerates the early G1 phase whereas Slug accelerates the late G1 phase. Blocking G1 phase is one of the basic conditions for the onset of EMT-related phenotype transitions (e.g., metastasis, acquring stemness). The discovery of this unexpected phenomenon (promoting G1 phase) typically reveals the heterogeneity of cancer cells. The onset of EMT-related phenotype transitions in cancer needs not only the induction and activation of SNAILs, but also some particular heredity alterations (genetic or epigenetic alterations, which cause heterogeneity). The new connection between heredity alteration (heterogeneity) and phenotype transition suggests a novel treatment strategy, the heredity alteration-directed specific target therapy. Further investigations need to be conducted to study the relevant heredity alterations. IntroductionCancer stem cell (CSC) is a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor (1). Although it has been proven that epithelial-mesenchymal transition (EMT) can generate cells with stem cell properties (2), it is still unknown which of the stem-like cancer cells are generated by these phenotype transitions.The function of Snail genes is best known for induction of EMT. Both in development and during carcinoma progression, Snail1 (Snail) is expressed at the onset of the transition, whereas Snail2 (Slug), Zeb genes, E47 and Twist are subsequently induced to maintain the migratory mesenchymal state (3). As transcriptional repressors, Snail and Slug can regulate the expression of genes mediating therapeutic resistance and acquiring of stem-like phenotype in ovarian cancer cells (4).Snail and Slug have complicated interactions with many key molecules. Snail can cause functional deficiency of p53 in tumor cells with mutant KRAS (5). We know GSK3β, the downstream molecule of Akt (6), can phosphorylate Snail to cause the degradation or the nuclear export of Snail (7). However, KRAS can interact with the PI3K/Akt pathway (8), and then affect GSK3β. Slug can escape degradation when p53 is mutant in lung cancer (9). In addition, the experssion of Slug can be regulated by mutant KRAS in colon cancer cells (10). Snail and Slug are also connected to other key molecules (e.g., EGFR, ERCC1) (11-13).Certain key molecules, including KRAS, p53, EGFR, ERCC1, are all connected to EMT (11,[14][15][16] and stem cell biology (17)(18)(19)(20). This makes the SNAIL-related ph...

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Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma

Cited by 209 publications

References 20 publications

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

SNAILs promote G1 phase in selected cancer cells

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