Identification of cancer initiating cells in
            <i>K-Ras</i>
            driven lung adenocarcinoma

Mainardi, Sara; Mijimolle, Nieves; Francoz, Sarah; Vicente-Dueñas, Carolina; Sánchez-Garcı́a, Isidro; Barbacid, Mariano

doi:10.1073/pnas.1320383110

Cited by 145 publications

(172 citation statements)

References 19 publications

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“…32 Later studies in mice with activated K-ras in SP-C + or CC10 + cells using conditional Cre ER knock-in alleles indicated that tumors arose only in the alveoli, although recombination occurred throughout the bronchioles, the BADJ and the bronchioalveolar stem cells, which are CC10/SP-C double-positive cells. 21,31 We found that KLF4 deletion increased the number of AT2 cells and enhanced K-ras-mediated lung tumorigenesis (Figures 2e-g and 4), consistent with the findings that AT2 cells are the major origin of lung cancer 22 and that K-ras regulates self-renewal of AT2 cells. 21 Compared with lesions at 8 weeks post infection, more adenomas and adenocarcinomas arose at 16 weeks in K-ras LSL-G12D/+ ;Klf4 fl/fl mice, whereas only trace amount of Figure 7a).…”

Section: Discussionsupporting

confidence: 88%

“…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: 66%

“…In a recent study, K-ras was activated by polr2a-Cre duct junction (BADJ), only alveolar lesions progressed to more advanced adenomas and adenocarcinomas, which were composed exclusively of SP-C + cells. 22 In another study, K-ras was activated in either AT2 cells or Clara cells by adenovirus-expressed SP-C-Cre or CC10-Cre. 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.…”

mentioning

confidence: 99%

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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: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 66%

mentioning

confidence: 99%

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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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“…They also give rise to lung adenocarcinoma induced by oncogenic Kras (1,(3)(4)(5). AT2 cells are derived from bipotent progenitor cells at the sacculation stage (1).…”

mentioning

confidence: 99%

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Zhang¹,

Newton²,

Kummerfeld³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

112

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Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4 COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.A lveolar type II (AT2) cells are a stem cell population that self renews and differentiates into alveolar type I (AT1) cells during lung homeostasis or in response to injury (1, 2). They also give rise to lung adenocarcinoma induced by oncogenic Kras (1, 3-5). AT2 cells are derived from bipotent progenitor cells at the sacculation stage (1). In the adult lung, mature AT2 cells also secrete surfactant phospholipids to maintain normal alveolar function. Sustained Kras activity stimulates the self-renewal of AT2 cells, which eventually leads to abnormal tissue growth (1). An AT2 gene-expression signature has been reported (6, 7), but it is unclear how the identity of AT2 cells is specified and maintained.Given that Ras/MAPK signaling is essential for the self-renewal of AT2 cells and for the initiation of lung adenocarcinoma, identification of the transcription factors that are activated by Ras in AT2 cells is a step toward defining the transcriptional programs underlying AT2 stemness. The PEA3 subgroup of the ETS family of transcription factors, comprised of ETS transcription variants 1, 4, and 5 (Etv1, Etv4, and Etv5) (8), is known to be engaged by Ras/MAPK signaling. Etv4 and Etv5 are expressed in distal lung epithelium during development and are involved in branching morphogenesis and epithelial cell differentiation (9-11). Alveolar epithelial cells in the adult lung also express Etv5 (7, 12), but a critical role for Etv5 in this setting remains elusive.PEA3 transcription factors are also implicated in tumorigenesis. Overexpression of ETV1 or ETV4 has been linked to prostate cancer (13,14), and stabilization of ETV1 by mutant, active tyrosine kinase receptor KIT is thought to drive an oncogenic program in gastrointestinal stromal tumors (GIST) (15). ETV1, ETV4, and ETV5 are labile proteins because of their regulation by the ubiquitin-proteasome system. In GIST, ETV1 protein is stabilized by activation of the Ras/MAPK pathway through an unkno...

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“…However, in more recent studies that targeted the expression of oncogenic Kras G12D only in cells expressing club cell secretory protein (CCSP), such as club cells and BASCs, or only in cells expressing surfactant protein C (SPC), such as AT2 cells and BASCs, AT2 cells seemed to be the only cells that were capable of giving rise to advanced ADC in the alveolar space, whereas club cells and BASCs seemed to be limited to driving bronchiolar hyperplasia within the same time frame 59 . Using these approaches, it is notable that changes in the cells of origin were evident when the genotype for tumour initiation was altered (for example, to include p53 loss) or if injury or inflammation were present during tumour initiation (for example, after adenovirus infection or after naphthalene-induced injury) 56,[59][60][61][62][63] . Injury or inflammation probably more closely mimics the scenario of tumour initiation in humans, in which environmental influences and ongoing injury occur in contrast to the relatively sterile mouse colony.…”

Section: Cell(s) Of Origin For Nsclc Heterogeneity At Tumour Initiationmentioning

confidence: 99%

Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases

Chen¹,

Fillmore²,

Hammerman³

et al. 2015

Nat Rev Cancer

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Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.Lung cancer results in the largest number of cancer-related deaths worldwide 1,2 . More than 85% of those cases are currently classified as non-small-cell lung cancer (NSCLC), for which the predicted 5-year survival rate is 15.9% -a figure that has only marginally improved during the past few decades 3 . Technological advances during the past decade, including the introduction of next-generation sequencing (NGS), the generation of multiple genetically engineered mouse models (GEMMs) of lung cancer and the construction of large databases characterizing the molecular features of human tumours, have transformed our view of NSCLC from histopathological descriptions to precise molecular and genetic identities that can be resolved to the single-cell level. In parallel, approaches and concepts from fields such as developmental biology, stem cell biology and immunology have deepened our knowledge of tumour development, cellular heterogeneity and interactions between the lung tumour and its surrounding microenvironment. These multidisciplinary Correspondence to P.S.H., C.F.K. and K.-K.W. phammerman@partners.org; carla.kim@childrens.harvard.edu; kwong1@partners.org. * These authors contributed equally to this work. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Cancer. Author manuscript; available in PMC 2017 December 04. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript efforts have enhanced our understanding of molecular disease mechanisms, thereby forming the rationales for targeting different cellular compartments simultaneously. Scientists and physicians have better tools than ever to pursue answers to two provocative questions: first, how can we define the specific subsets of NSCLC that differ by cellular and molecular composition? Second, how can we effectively control lung cancer growth for each specific subset of NSCLC? In this Review, we discuss how data that are derived from technological advances in lung cancer genomics, mouse modelling of cancers and tumour microenvironment studies might be used to improve the survival of patients with NSCLC through the development of novel therapeutic strategies. Defining NSCLC subsetsNSCLC is currently defined by pathological characteristics. The two...

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Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma

Cited by 145 publications

References 19 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

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases

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