13 research outputs found
Prevention of early stage Kras-mutant lung adenocarcinoma via targeted KrasG12D inhibition
https://openworks.mdanderson.org/sumexp22/1118/thumbnail.jp
Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations
Lung adenocarcinomas (LUADs) with somatic mutations in the KRAS oncogene comprise the most common molecular subtype of lung cancer in smokers and present with overall dismal prognosis and resistance to most therapies. Our group recently demonstrated that tobacco carcinogen-exposed mice with knockout of the airway lineage G-protein coupled receptor, Gprc5a, develop LUADs with somatic mutations in Kras. Earlier work has suggested that cancer stem cells (CSCs) play crucial roles in clonal evolution of tumors and in therapy resistance. To date, our understanding of CSCs in LUADs with somatic Kras mutations remains lagging. Here we derived CSCs (as spheres in 3D cultures) with self-renewal properties from a murine Kras-mutant LUAD cell line we previously established from a tobacco carcinogen-exposed Gprc5a−/− mouse. Using syngeneic Gprc5a−/− models, we found that these CSCs, compared to their parental isoforms, exhibited increased tumorigenic potential in vivo, particularly in female animals. Using whole-transcriptome sequencing coupled with pathways analysis and confirmatory PCR, we identified gene features (n = 2,600) differentially expressed in the CSCs compared to parental cells and that were enriched with functional modules associated with an augmented malignant phenotype including stemness, tumor-promoting inflammation and anti-oxidant responses. Further, based on in silico predicted activation of GSK3β in CSCs, we found that tideglusib, an irreversible inhibitor of the kinase, exhibited marked anti-growth effects in the cultured CSCs. Our study underscores molecular cues in the pathogenesis of Kras-mutant LUAD and presents new models to study the evolution, and thus high-potential targets, of this aggressive malignancy
Meeting report: the road to science-based policy - ESOF through the eyes of young scientists
Communication and common understanding between politicians, scientists, and the society can lead to evidence-based science policy, a core principle that guides high caliber research and open innovation for a sustainable future
Cell-by-Cell: Unlocking Lung Cancer Pathogenesis
For lung cancers, cellular trajectories and fates are strongly pruned by cell intrinsic and extrinsic factors. Over the past couple of decades, the combination of comprehensive molecular and genomic approaches, as well as the use of relevant pre-clinical models, enhanced micro-dissection techniques, profiling of rare preneoplastic lesions and surrounding tissues, as well as multi-region tumor sequencing, have all provided in-depth insights into the early biology and evolution of lung cancers. The advent of single-cell sequencing technologies has revolutionized our ability to interrogate these same models, tissues, and cohorts at an unprecedented resolution. Single-cell tracking of lung cancer pathogenesis is now transforming our understanding of the roles and consequences of epithelial-microenvironmental cues and crosstalk during disease evolution. By focusing on non-small lung cancers, specifically lung adenocarcinoma subtype, this review aims to summarize our knowledge base of tumor cells-of-origin and tumor–immune dynamics that have been primarily fueled by single-cell analysis of lung adenocarcinoma specimens at various stages of disease pathogenesis and of relevant animal models. The review will provide an overview of how recent reports are rewriting the mechanistic details of lineage plasticity and intra-tumor heterogeneity at a magnified scale thanks to single-cell studies of early- to late-stage lung adenocarcinomas. Future advances in single-cell technologies, coupled with analysis of minute amounts of rare clinical tissues and novel animal models, are anticipated to help transform our understanding of how diverse micro-events elicit macro-scale consequences, and thus to significantly advance how basic genomic and molecular knowledge of lung cancer evolution can be translated into successful targets for early detection and prevention of this lethal disease
Iron dynamics and microbiome dysbiosis during tobacco-associated lung adenocarcinoma development
https://openworks.mdanderson.org/sumexp21/1096/thumbnail.jp
Smoking and Lung Cancer: A Geo-Regional Perspective
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This “cocktail” of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon
Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models
Lung cancer development relies on cell proliferation and migration, which in turn requires interaction with extracellular matrix (ECM) components such as glycosaminoglycans (GAGs). The mechanisms through which GAGs regulate cancer cell functions are not fully understood but they are, in part, mediated by controlled interactions with cytokines and growth factors (GFs). In order to mechanistically understand the effect of the degree of sulfation (DS) of GAGs on lung adenocarcinoma (LUAD) cells, we synthesized sulfated alginate (AlgSulf) as sulfated GAG mimics with DS = 0.0, 0.8, 2.0, and 2.7. Human (H1792) and mouse (MDA-F471) LUAD cell lines were treated with AlgSulf of various DSs at two concentrations 10 and 100 µg/mL and their anti-tumor properties were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue exclusion, and wound healing assays for 2D models and sphere formation assay for the 3D model. The proliferation and number of live MDA-F471 cells at the concentration of 100 µg/mL decreased significantly with the increase in the DS of biomimetic GAGs. In addition, the increase in the DS of biomimetic GAGs decreased cell migration (p < 0.001 for DS = 2.0 and 2.7 compared to control) and decreased the diameter and number of spheres formed (p < 0.001). The increased DS of biomimetic GAGs attenuated the expression of cancer stem cell (CSC)/progenitor markers in the 3D cultures. In conclusion, GAG-mimetic AlgSulf with increased DS exhibit enhanced anti-proliferative and migratory properties while also reducing growth of KRAS-mutant LUAD spheres in vitro. We suggest that these anti-tumor effects by GAG-mimetic AlgSulf are possibly due to differential binding to GFs and consequential decreased cell stemness. AlgSulf may be suitable for applications in cancer therapy after further in vivo validation
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Early Diagnosis and Screening for Lung Cancer
Cancer interception refers to actively blocking the cancer development process by preventing progression of premalignancy to invasive disease. The rate-limiting steps for effective lung cancer interception are the incomplete understanding of the earliest molecular events associated with lung carcinogenesis, the lack of preclinical models of pulmonary premalignancy, and the challenge of developing highly sensitive and specific methods for early detection. Recent advances in cancer interception are facilitated by developments in next-generation sequencing, computational methodologies, as well as the renewed emphasis in precision medicine and immuno-oncology. This review summarizes the current state of knowledge in the areas of molecular abnormalities in lung cancer continuum, preclinical human models of lung cancer pathogenesis, and the advances in early lung cancer diagnostics