Alpha-Smooth Muscle Actin (ACTA2) Is Required for Metastatic Potential of Human Lung Adenocarcinoma

Lee, Hye Won; Park, Young Mi; Lee, Se Jeong; Cho, Hyun Jung; Kim, Duk-Hwan; Lee, Jung-Il; Kang, Myeung-Soo; Seol, Ho Jun; Shim, Young Mog; Nam, Do‐Hyun; Kim, Hyeon Ho; Joo, Kyeung Min

doi:10.1158/1078-0432.ccr-13-1181

Cited by 114 publications

(85 citation statements)

References 31 publications

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“…S4C). ACTA2 has been implicated in promoting migration and metastasis (Lee et al 2013). HPL1D cells overexpressing either the ACTA2 or PLAG1-ACTA2 transgene displayed increased chemotaxis and invasion through Matrigel, and PLAG1-ACTA2 appeared to be functionally indistinguishable from ACTA2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, in the lymph node biopsy from 2013, there was up-regulation of ACTA2 and the difference in expression between ACTA2 and the fusion transcript was less than twofold. The elevated expression of ACTA2 has been implicated in increased metastatic potential and poor outcome in human lung adenocarcinoma patients and the role of ACTA2 in these processes has been validated in vitro (Lee et al 2012, 2013). We show that overexpression of PLAG1-ACTA2 in immortalized lung epithelial cells resulted in increased chemotaxis and migration (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

Biswas

Gao

Cultraro

et al. 2016

Cold Spring Harb Mol Case Stud

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We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an “exceptional responder” lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies showed increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy because of L869R mutation and increased migration because of ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a subclone metastasized early from the primary site and evolved independently in lymph nodes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

Biswas

Gao

Cultraro

et al. 2016

Cold Spring Harb Mol Case Stud

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show abstract

“…Serial 5-mm-thick sections from each FFPE block were processed for hematoxylin and eosin (H&E) staining and were examined by a specialized pathologist. IHC was performed as previously described (20) using the following primary antibodies: thyroid transcription factor-1 (TTF-1; Abcam; ab40880, 1:1,000), Napsin-A (Abcam; ab133249, 1:250), and p63 (Abcam; ab53039, 1:200).…”

Section: Histology and Ihcmentioning

confidence: 99%

Patient-Derived Xenografts from Non–Small Cell Lung Cancer Brain Metastases Are Valuable Translational Platforms for the Development of Personalized Targeted Therapy

Lee

et al. 2015

Clinical Cancer Research

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Purpose: The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies.Experimental Design: We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment.Results: NSCLC brain metastases (n ¼ 34) showed a significantly higher successful PDX establishment rate than primary specimens (n ¼ 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions.Conclusions: Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments.

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“…Indeed, analyzing mass spectra of actin purified using LC-224-coated magnetic particles from the samples of a lung adenocarcinoma patient revealed that all actin cytoplasmic 1 have a post-translational modification: histidine at position 73 is methylated (Figure S6). Actin is known as a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma 33 . The driving force for membrane protrusion is localized polymerization of sub-membrane actin filaments.…”

Section: Resultsmentioning

confidence: 99%

DNA Aptamers for the Characterization of Histological Structure of Lung Adenocarcinoma

Zamay

Ivanchenko

Zamay

et al. 2017

Molecular Therapy - Nucleic Acids

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Nucleic acid aptamers are becoming popular as molecular probes for identification and imaging pathology and, at the same time, as a convenient platform for targeted therapy. Recent studies have shown that aptamers may be effectively used for tumor characterization and as commercially available monoclonal antibodies. Here we present three DNA aptamers binding to whole transformed lung cancer tissues, including tumor cells, connective tissues, and blood vessels. Protein targets have been revealed using affinity purification followed by mass spectrometry analyses, and they have been validated using a panel of correspondent antibodies and 3D imaging of tumor tissues. Each of the proteins targeted by the aptamers is involved in cancer progression and most of them are crucial for lung adenocarcinoma. We propose the use of these aptamers in aptahistochemistry for the characterization of the histological structure of lung adenocarcinoma. The value of the presented aptamers is their application together or separately for indicating the spread of neoplastic transformation, for complex differential diagnostics, and for targeted therapy of the tumor itself as well as all transformed structures of the adjacent tissues. Moreover, it has been demonstrated that these aptamers could be used for intraoperative tumor visualization and margin assessment.

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Alpha-Smooth Muscle Actin (ACTA2) Is Required for Metastatic Potential of Human Lung Adenocarcinoma

Cited by 114 publications

References 31 publications

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

Patient-Derived Xenografts from Non–Small Cell Lung Cancer Brain Metastases Are Valuable Translational Platforms for the Development of Personalized Targeted Therapy

DNA Aptamers for the Characterization of Histological Structure of Lung Adenocarcinoma

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