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X. Han
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-069 - LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-Small Cell Lung Cancer Plasticity and Therapeutic Response (ID 705)
09:30 - 09:30 | Author(s): X. Han
- Abstract
Background:
LKB1 regulates both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non-small cell lung cancer (NSCLC).
Methods:
Mouse Colony, Mouse Treatment and Tumor Analyses Statistical Analysis Hematoxylin and Eosin (HE) Staining and Immunohistochemistry (IHC) Bioinformatics Analysis Cell Lines and In vitro Assays ShRNA, Plasmids, Lentivirus Production and Infection Analysis of Human Lung ADC and Ad-SCC Specimens Western Blotting Enzymatic Activity Assays and Liquid Chromatography-tandem Mass Spectrometry (LC-MS) Analysis Oil red O Staining Reverse Transcription and Quantitative PCR Analysis
Results:
Here in KRAS/LKB1 (KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can modulate ADC-to-SCC transdifferentiation (AST). Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials towards metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation.
Conclusion:
This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.
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P1.04-092 - LKB1 Inactivation Confers Human Lung Adenocarcinoma with Strong Plasticity for Squamous Transdifferentiation (ID 1012)
09:30 - 09:30 | Author(s): X. Han
- Abstract
Background:
Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are considered as two distinct subtypes of lung cancer and derived from different types of lung epithelial cells and featured with different biomarker expression. Interestingly, there exist certain lung tumors so called adenosquamous cell carcinoma (Ad-SCC) containing mixed both adenomatous and squamous pathologies; more importantly, these two different pathologies within a single tumor are consistently shown to have identical gene mutations. In consideration the fact that most tumors are derived from a single epithelial cell, it’s reasonable to hypothesize that there must exist lineage transition between ADC and SCC subtypes. However, this fundamental question remains unanswered due to the difficulty of study of human clinical samples. Indeed, most studies of clinical samples can only provide indirect evidences to support this hypothesis. Taking advantage of mouse models mimicking human lung cancer, we have recently successfully shown that inactivation of a tumor suppressor LKB1 confers mouse lung ADC with strong plasticity and makes them transdifferentiate into SCC through mixed Ad-SCC as intermediates (Han XK, et al. Nat Commun, 2014). However, whether there exists a phenotypic transition from ADC to SCC in human lung cancer remains unknown.
Methods:
Immunohistochemical analyses Integrative genomic analyses Establishement of patient-derived tumor xenograft model Statistic Analyses
Results:
not applicable.
Conclusion:
We pathologically analyzed a large cohort of human NSCLC samples and carefully evaluate the prevalence of mixed pathologies in context with LKB1 genetic inactivation. Moreover, we took advantage of the established lung ADC PDX mouse models to perform serial transplantation w/o the interfere of essential signaling pathways identified from de novo animal model study and test if possible that human ADC with LKB1 inactivation can progress and transdifferentiate into SCC. Based on our current understanding of this type of phenotypic transition in mice as well as the resources and systems established in the lab, we here succeed in proving the transdifferentiation of human ADC to SCC.
