scholarly journals Development and Characterization of Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases

2020 ◽  
Author(s):  
Andrew M. Baschnagel ◽  
Saakshi Kaushik ◽  
Arda Durmaz ◽  
Steve Goldstein ◽  
Irene M. Ong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Small Cell ◽  
Growth Delay ◽  
Small Cell Lung

AbstractIntroductionThe purpose of this study was to establish and characterize a direct-from patient-derived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases.MethodsSurgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants into immunodeficient mice. Histology and DNA loci were compared between original tumor and subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant therapeutic targets were identified. Tumor growth rates were assessed following treatment with radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established.ResultsNine NSCLC brain metastases PDXs were established. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumor and subcutaneous and intracranial tumors. Short tandem repeat analysis demonstrated strong concordance between patient tumors and subsequent PDX passages. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples. Significant growth inhibition occurred with radiation, with selumetinib in tumors harboring KRAS G12C mutations and with savolitinib in a tumor with MET exon 14 skipping mutation. The combination of radiation and savolitinib resulted in significant tumor growth delay compared to radiation or savolitinib alone our MET exon 14 skipping mutation PDX. Early passage cell strains showed high consistency between patient and PDX tumors.ConclusionWe have established a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

scholarly journals Nicotine Induces Resistance to Erlotinib Therapy in Non-Small-Cell Lung Cancer Cells Treated with Serum from Human Patients

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 282 ◽  
Author(s):  
Tatsuya Imabayashi ◽  
Junji Uchino ◽  
Hisayuki Osoreda ◽  
Keiko Tanimura ◽  
Yusuke Chihara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Cancer Cell Lines ◽  
Small Cell ◽  
Small Cell Lung ◽  
Erlotinib Therapy

Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs by treating cancer cell lines with erlotinib, afatinib, or osimertinib, and serum collected from smokers within 30 min of smoking and that from a non-smoker as a control. We also assessed erlotinib resistance by treating PC9 cells exposed to serum from a smoker or a non-smoker, or serum from an erlotinib user. Treatment of the cancer cell lines with serum from smokers induced significant erlotinib resistance, compared with the control (p < 0.05). Furthermore, serum samples with a high concentration of cotinine (a nicotine exposure indicator) demonstrated stronger erlotinib resistance than those with low concentrations. Similar to the observations with erlotinib treatment of cell lines, the analysis of serum from erlotinib users revealed that smokers demonstrated significantly reduced sensitivity to erlotinib (p < 0.001). In conclusion, our present results support the hypothesis that smoking contributes to resistance to erlotinib therapy in non-small-cell lung cancer.

scholarly journals LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 705 ◽  
Author(s):  
Cédric Zeltz ◽  
Elena Pasko ◽  
Thomas R. Cox ◽  
Roya Navab ◽  
Ming-Sound Tsao
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Tumor Stroma ◽  
Small Cell ◽  
Matrix Remodeling ◽  
Small Cell Lung

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

scholarly journals PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53

2011 ◽  
Vol 17 (9) ◽  
pp. 2830-2841 ◽  
Author(s):  
Roza Zandi ◽  
Galina Selivanova ◽  
Camilla Laulund Christensen ◽  
Thomas Alexander Gerds ◽  
Berthe Marie Willumsen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Growth Delay ◽  
Mutant P53 ◽  
Small Cell Lung ◽  
Tumor Growth Delay

scholarly journals Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew M. Baschnagel ◽  
Saakshi Kaushik ◽  
Arda Durmaz ◽  
Steve Goldstein ◽  
Irene M. Ong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Model System ◽  
Small Cell ◽  
Small Cell Lung ◽  
In Vivo Models

AbstractNon-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

scholarly journals Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

2015 ◽  
Vol 112 (11) ◽  
pp. E1288-E1296 ◽  
Author(s):  
Anthony C. Faber ◽  
Anna F. Farago ◽  
Carlotta Costa ◽  
Anahita Dastur ◽  
Maria Gomez-Caraballo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Small Cell ◽  
High Expression ◽  
Small Cell Lung ◽  
Genetically Engineered Mouse Model

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.

scholarly journals Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

BMC Cancer ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Jacob E Koskimaki ◽  
Emmanouil D Karagiannis ◽  
Benjamin C Tang ◽  
Hans Hammers ◽  
D Neil Watkins ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Collagen Iv ◽  
Small Cell ◽  
Small Cell Lung

The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

2019 ◽  
Vol 22 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Gang Chen ◽  
Bo Ye
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

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