Life in the Fast Lane: Mammalian Disease Models in the Genomics Era

Dow, Lukas E.; Lowe, Scott W.

doi:10.1016/j.cell.2012.02.023

Cited by 71 publications

(58 citation statements)

References 82 publications

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“…Genetically engineered mouse models (GEMMs) are powerful tools for the study of gene function in disease (21,22). We previously optimized an efficient pipeline that implements recombinase-mediated cassette exchange to introduce tet-responsive shRNAs into embryonic stem cells at a defined genomic locus, thereby providing a platform to explore the requirement for sustained gene loss in disease progression and maintenance (23,24).…”

Section: Resultsmentioning

confidence: 99%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

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

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Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracyclineregulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

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Section: Resultsmentioning

confidence: 99%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

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

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“…Three-dimensional culture techniques might also offer a new way to propagate normal and tumorigenic lung cells to better probe vulnerabilities of tumour cells 49,73 . Multiple in vivo models using mice to recapitulate lung cancer disease processes and treatment responses have been generated, including GEMMs harbouring specific genetic aberrations that have been identified in human tumours 55,80 …”

Section: Integrated Therapies For Nsclc Target Validation and Patientmentioning

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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“…The application of genomic technologies to the study of cancers has revolutionized our understanding of the genetic landscapes of tumors (1,2); however, functional studies are required to make sense of these cataloguing efforts to determine how different combinations of the many candidate genetic mutations dictate tumor phenotypes and to provide accurate models that can be used in preclinical studies to identify mutation-specific therapies. Germline genetic manipulation techniques have allowed the generation of lines of mice in which genes can be deleted, mutated, silenced, or overexpressed in temporal and cell-type-specific manners (3). These approaches have provided many insights into cancer development and progression; however, the generation of genetically modified mice and their interbreeding to generate compound mutants are time consuming and costly processes.…”

Section: Introductionmentioning

confidence: 99%