Early Steps in Lung Oncogenesis最新文献

{"title":"Abstract IA07: Influence of cancer initiation on tumor progression in SCLC","authors":"Dian Yang, M. Winslow, J. Sage","doi":"10.1158/1557-3265.AACRIASLC18-IA07","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA07","url":null,"abstract":"The vast majority of cancer patients die from metastatic disease, but the molecular and cellular mechanisms that drive metastatic progression often remain poorly understood. Small cell lung cancer (SCLC) is a neuroendocrine form of lung cancer and one of the most metastatic and lethal cancers. Most SCLC patients are usually first diagnosed when they already have metastatic disease, and SCLC tumors are thus thought to acquire metastatic ability early in the course of tumor development. However, how early events shape the evolution and metastatic progression of SCLC is largely unknown. We will present evidence, using genetically engineered mouse models of SCLC, that distinct mechanisms drive metastatic progression depending on the cell of origin. In one mouse model, we found that tumors gain metastatic ability through amplification of the transcription factor Nfib; this amplification is accompanied by a striking opening of the chromatin at many sites in the genome. In the second model, metastatic progression is not associated with Nfib-driven chromatin alterations. Gene expression profiling studies reveal distinct mechanisms of metastatic progression in the two groups, as well as markers predictive of the two metastatic paths. Our data indicate that Nfib-independent metastases arise from pulmonary neuroendocrine cells. These observations demonstrate that the identity of tumor-initiating cells can determine the molecular mechanisms of tumor evolution. Citation Format: Dian Yang, Monte M. Winslow, Julien Sage. Influence of cancer initiation on tumor progression in SCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA07.","PeriodicalId":236321,"journal":{"name":"Early Steps in Lung Oncogenesis","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125956709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA06: Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization","authors":"J. Rahman, X. Ji, C. Patel, Jamey D. Young, P. Massion","doi":"10.1158/1557-3265.AACRIASLC18-IA06","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA06","url":null,"abstract":"Airway epithelial cells are prone to assault by risk factors and considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushings specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified over 300 proteins with a significant trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for seven months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results also pointed towards a fundamental role of glutamine and cysteine metabolism in lung cancer progression. Two amino acid transporters, specifically SLC1A5 and SLC7A11, captured our attention for their high level of expression in lung cancer. These transporters are associated with worse survival in lung cancer. A small-molecular inhibitor of SLC1A5 prevents tumor progression in nude mice, and a glutaminase inhibitor CB-839 exhibits radiosensitization to lung cancer cells, an effect that may be mediated by decreased GSH production. Taken together, these studies provide a rationale for new chemopreventive strategies, selection of patients for surveillance programs, and determining how metabolic reprogramming may contribute genomic instability a requirement to cancer development. Further investigation into how glutamine and cystine metabolism contribute to lung cancer development and progression may lead to novel early-interception strategies in lung cancer. This work is supported by NCI CA186145, CA152662, and DoD W81XWH-11-2-0161. Citation Format: Jamshed Rahman, Xiangming Ji, Chirayu Patel, Jamey Young, Pierre P. Massion. Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA06.","PeriodicalId":236321,"journal":{"name":"Early Steps in Lung Oncogenesis","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130144733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA05: Early steps in lung oncogenesis","authors":"S. Janes","doi":"10.1158/1557-3265.AACRIASLC18-IA05","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA05","url":null,"abstract":"Lung cancer is the biggest cancer killer of men and women, and there has been no improvement in survival over the last 50 years. To reduce the mortality of lung cancer, we need to both detect and treat it earlier, ideally at a preinvasive cancer stage before progression into full-blown invasive cancer. This would allow us to initiate treatment in a timely manner, increasing the chances of cure and saving lives. Lung cancers arise from preinvasive lesions but, interestingly, not all these lesions progress to cancer. We believe that understanding the differences between the lesions that progress to invasive cancer and those that disappear will direct us to the key proteins and genes that are mis-expressed, or inappropriately switched on or off, that lead to invasive cancer formation. My talk will outline studies that shed new understanding on how lung cancer develops and identify novel biological markers that accurately predict whether a lesion will eventually grow into a cancer. This, I hope, will enable targeting potential therapies to those patients with lesions that are likely to progress and identify the key genes and proteins associated with cancer development, thereby opening the possibility of developing chemoprophylactic therapeutic approaches to prohibit cancer development. Citation Format: Samuel M. Janes. Early steps in lung oncogenesis [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA05.","PeriodicalId":236321,"journal":{"name":"Early Steps in Lung Oncogenesis","volume":"115 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130390410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR02: Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer","authors":"T. Oike, Y. Kanke, Amelia L. Parker, M. Haznadar, K. Krausz, E. Bowman, A. Robles, F. Gonzalez, C. Harris","doi":"10.1158/1557-3265.AACRIASLC18-PR02","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-PR02","url":null,"abstract":"Lung cancer is the leading cause of cancer-related death worldwide. With the advent of low-dose computed tomography screening, it is expected that the number of lung cancers diagnosed at an early stage will rise sharply. The recommended treatment for stage I non-small cell lung cancer (NSCLC) patients is tumor resection, which may be followed by chemotherapy in patients with pathologically high-risk, margin-negative stage IB tumors. Still, up to 30% surgically treated stage I patients experience recurrence leading to death. Therefore, biomarkers that molecularly categorize stage I patients after tumor resection and stratify high-risk patients who may benefit from adjuvant chemotherapy would lead to improved clinical management. We previously conducted metabolomic profiling of urines collected from 469 NSCLC patients and 536 population controls using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) and found that creatine riboside, a novel metabolite identified by the study, is significantly elevated in stage I and II NSCLC patients compared to controls. We also found that creatine riboside levels are 19-fold higher in tumor tissues compared to adjacent normal lung tissues (P 2 =0.87 by Spearman’s rank order test). These data indicate that creatine riboside may be a product of deregulated tumor metabolism that is detectable in urine, making urinary creatine riboside a potentially useful liquid biopsy biomarker for surveillance after surgery in early stage NCSLC patients. To further evaluate the utility of creatine riboside as a liquid biopsy biomarker, urines from 34 stage I and II NSCLC patients from Lung Cancer Biospecimen Resource Network (LCBRN), collected at the time of diagnosis and 6, 12, 18 and 24 months after surgery, were evaluated in the current study. The urinary levels of creatine riboside were quantitated using UPLC-MS/MS and were analyzed for association with cancer-specific survival and disease-free survival. As a result, in non-recurrent cases (n=23), creatine riboside levels showed a significant decreasing trend over 24 months after surgery (P=0.03). These data further support previous evidence that creatine riboside is a product of deregulated tumor metabolism that can be detected in urine. In addition, Kaplan Meier survival estimates demonstrated that high creatine riboside levels at the time of diagnosis correlated significantly with worse cancer-specific survival and disease-free survival (P=0.005 and P=0.003, respectively). In summary, urinary creatine riboside may have potential as a liquid biopsy biomarker for early stage NSCLC that aids surveillance after surgery as well as to stratify patients with worse prognosis. This abstract is also being presented as Poster A18. Citation Format: Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Kristopher W. Krausz, Elise D. Bowman, Ana I. Robles, Frank J. Gonzalez, Curtis C. Harris. Diagnostic and prognostic utility of urinary creatine ribos","PeriodicalId":236321,"journal":{"name":"Early Steps in Lung Oncogenesis","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132384018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}