Publications by authors named "Adi F Gazdar"

250 Publications

SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas.

J Natl Cancer Inst 2021 Sep 15. Epub 2021 Sep 15.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: About 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN, a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD.

Methods: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN in was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were two-sided.

Results: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidential interval = 1.12 to 15.86; likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1 (PD-1)-positive lymphocytes. SRGN regulated expression of PD-L1, as well as proinflammatory cytokines including Interleukin-6 (IL-6), Interleukin-8 (IL-8), and C-X-C motif chemokine 1 (CXCL1) in LUAD cell lines, and increased migratory and invasive properties of LUAD cells and fibroblasts, and enhanced angiogenesis. SRGN was induced by DNA de-methylation resulting from Nicotinamide N-methyltransferase (NNMT)-mediated impairment of methionine metabolism.

Conclusion: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD.
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http://dx.doi.org/10.1093/jnci/djab183DOI Listing
September 2021

Cell-autonomous immune gene expression is repressed in pulmonary neuroendocrine cells and small cell lung cancer.

Commun Biol 2021 03 9;4(1):314. Epub 2021 Mar 9.

Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.

Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed "variant" due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings may help guide the design of treatment regimens in SCLC.
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http://dx.doi.org/10.1038/s42003-021-01842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943563PMC
March 2021

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer.

J Clin Invest 2021 01;131(1)

Children's Medical Center Research Institute.

MYC stimulates both metabolism and protein synthesis, but how cells coordinate these complementary programs is unknown. Previous work reported that, in a subset of small-cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here, we demonstrated that primary MYChi human SCLC tumors also contained abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH linked the metabolic and protein synthesis outputs of oncogenic MYC. Coexpression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functioned as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant MYChi SCLC.
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http://dx.doi.org/10.1172/JCI139929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773395PMC
January 2021

ClickGene: an open cloud-based platform for big pan-cancer data genome-wide association study, visualization and exploration.

BioData Min 2019 26;12:12. Epub 2019 Jun 26.

1School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072 China.

Tremendous amount of whole-genome sequencing data have been provided by large consortium projects such as TCGA (The Cancer Genome Atlas), COSMIC and so on, which creates incredible opportunities for functional gene research and cancer associated mechanism uncovering. While the existing web servers are valuable and widely used, many whole genome analysis functions urgently needed by experimental biologists are still not adequately addressed. A cloud-based platform, named CG (ClickGene), therefore, was developed for DIY analyzing of user's private in-house data or public genome data without any requirement of software installation or system configuration. CG platform provides key interactive and customized functions including Bee-swarm plot, linear regression analyses, Mountain plot, Directional Manhattan plot, Deflection plot and Volcano plot. Using these tools, global profiling or individual gene distributions for expression and copy number variation (CNV) analyses can be generated by only mouse button clicking. The easy accessibility of such comprehensive pan-cancer genome analysis greatly facilitates data mining in wide research areas, such as therapeutic discovery process. Therefore, it fills in the gaps between big cancer genomics data and the delivery of integrated knowledge to end-users, thus helping unleash the value of the current data resources. More importantly, unlike other R-based web platforms, Dubbo, a cloud distributed service governance framework for 'big data' stream global transferring, was used to develop CG platform. After being developed, CG is run on an independent cloud-server, which ensures its steady global accessibility. More than 2 years running history of CG proved that advanced plots for hundreds of whole-genome data can be created through it within seconds by end-users anytime and anywhere. CG is available at http://www.clickgenome.org/.
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http://dx.doi.org/10.1186/s13040-019-0202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595587PMC
June 2019

Comparison of four DLL3 antibodies performance in high grade neuroendocrine lung tumor samples and cell cultures.

Diagn Pathol 2019 May 20;14(1):47. Epub 2019 May 20.

Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010, Graz, Austria.

Background: Small cell lung cancer (SCLC) is usually diagnosed in the advanced stage. It has a very poor prognosis, with no advancements in therapy in the last few decades. A recent phase 1 clinical study, using an antibody-drug conjugate directed against DLL3, showed promising results. A prerequisite for this therapy is an immunohistochemical test for DLL3 expression. The antibody used in the clinical trial was bound to a specific platform, which is not available in all pathology laboratories. In this study, the expression of DLL3 was analyzed using different DLL3 antibodies in high-grade neuroendocrine tumors of the lung and cell cultures. Additionally, correlation of DLL3 expression with Rb1 loss and TP53 mutation was evaluated.

Methods: The study cohort consisted of surgically resected cases, 24 SCLC and 29 large cell neuroendocrine carcinoma (LCNEC), from which tissue microarrays (TMAs) were constructed. The validation cohort included 46 SCLC samples, mostly small biopsies. Additionally, well-characterized SCLC cell lines were used. Immunohistochemical analysis was performed using four different DLL3 antibodies, as well as TP53 and Rb1 antibodies. Expression was evaluated microscopically and manually scored.

Results: The comparison of all DLL3 antibodies showed poor results for the overall agreement, as well as positive and negative agreement. Differences were observed regardless of the applied cut-off values and the tumor type. The antibody used in the clinical trial was the only which always positively stained the tumor cells obtained from cell cultures with known DLL3 expression and was negative on cells that did not express DLL3. There was no correlation between p53 and DLL3 expression in SCLC and LCNEC. RB1 loss in SCLC showed statistical significant correlation with the DLL3 positivity (p = 0.037), while no correlation was found in LCNEC.

Conclusion: The DLL3 antibody used in the clinical trial demonstrated superiority in the detection of DLL3 expression. Cell cultures, which can be used for DLL3 antibodies as positive and negative probes, were established. Evidence of DLL3 expression in high proportions of patients with LCNEC might provide basis for studies of new therapy options in this group of patients.
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http://dx.doi.org/10.1186/s13000-019-0827-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528329PMC
May 2019

Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.

Nat Rev Cancer 2019 05;19(5):289-297

University of Texas Southwestern Medical Center, Dallas, TX, USA.

Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.
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http://dx.doi.org/10.1038/s41568-019-0133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538259PMC
May 2019

Small cell lung cancers made from scratch.

J Exp Med 2019 03 13;216(3):476-478. Epub 2019 Feb 13.

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX

In this issue of , Chen et al. (https://doi.org/10.1084/jem.20181155) describe a new approach for the transformation of human pluripotent embryonic stem cells (hESCs) into neuroendocrine (NE) tumors of the lung closely resembling human small cell lung cancer (SCLC). Another recent study uses a different method to transform fully differentiated normal human cells into high-grade NE tumors (Park et al. 2018. https://doi.org/10.1126/science.aat5749). These approaches and their models provide important new resources for developing diagnostic, preventative, and therapeutic approaches for high-grade NE tumors.
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http://dx.doi.org/10.1084/jem.20182216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400528PMC
March 2019

A quantitative method for assessing smoke associated molecular damage in lung cancers.

Transl Lung Cancer Res 2018 Aug;7(4):439-449

Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.

Background: While tobacco exposure is the cause of the vast majority of lung cancers, an important percentage arise in lifetime never smokers. Documenting the precise extent of tobacco induced molecular changes may be of importance. Also, the contribution of environmental tobacco smoke (ETS) is difficult to assess.

Methods: We developed and validated a quantitative method to assess the extent of tobacco related molecular damage by combing the most characteristic changes associated with tobacco smoke, the tumor mutation burden (TMB) and type of molecular changes present in lung cancers. Using maximum entropy (MaxEnt) as a classifier, we developed a F score. F score values >0 were considered to show evidence of tobacco related molecular damage, while values ≤0 were considered to lack evidence of tobacco related molecular damage. Compared to the stated patient tobacco exposure histories, the F scores had sensitivity, specificity and accuracy values of 85-87%. Using this method, we analyzed public data sets of lung adenocarcinoma (LUAD), lung squamous cell (LUSC) and small cell lung cancer (SCLC).

Results: Less than 10% of LUSCs and SCLCs had negative F scores, while 27% to 35% of LUADs had positive scores. The F score showed a highly significant downward trend when LUADs were subdivided into the following categories: ever, reformed ≤15 years, reformed >15 years and never smokers. Most of the examined bronchial carcinoids (a lung cancer type not associated with smoke exposure) had negative F scores. In addition, most LUADs with EGFR mutations had negative F scores, while almost all with KRAS mutations had positive scores.

Conclusions: We have established and validated a quantitative assay that will be of use in assessing the presence and degree of smoke associated molecular damage in lung cancers arising in ever and never smokers.
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http://dx.doi.org/10.21037/tlcr.2018.07.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131178PMC
August 2018

Preface: lung cancer in never smokers.

Authors:
Adi F Gazdar

Transl Lung Cancer Res 2018 Aug;7(4):437-438

UT Southwestern Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.21037/tlcr.2018.06.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131179PMC
August 2018

Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition.

Cancer Discov 2018 11 4;8(11):1422-1437. Epub 2018 Sep 4.

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.

, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad deletion in mouse neuroendocrine cells cooperated with loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that loss results in reduced expression of tight junction and cell adhesion genes, including , across neuroendocrine tumor types, whereas suppression of promoted transformation in SCLC. and other adhesion genes exhibited reduced histone acetylation with inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of -deficient SCLC exhibited exceptional responses to Pracinostat Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy. Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in -deleted tumors. These data provide a rationale for selectively treating -mutant SCLC with HDAC inhibitors. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294438PMC
November 2018

Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers.

Cell Metab 2018 09 28;28(3):369-382.e5. Epub 2018 Jun 28.

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1 and ASCL1), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1 cells and tumors from genetically engineered mice. ASCL1 tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1 SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1 cell growth in culture, selectively reduced growth of ASCL1 xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1/MYC SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.
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http://dx.doi.org/10.1016/j.cmet.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125205PMC
September 2018

Retraction notice to "Sun exposure related methylation in malignant and non-malignant skin lesions" [Cancer Letters 245/1-2 (2007) 112-120].

Cancer Lett 2018 Sep;432:272

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, Texas75390-8593, USA; Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA.

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http://dx.doi.org/10.1016/j.canlet.2018.07.010DOI Listing
September 2018

Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer.

Oncotarget 2018 Mar 14;9(18):14251-14267. Epub 2018 Feb 14.

Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Fibulin 5 (FBLN5) is an extracellular matrix glycoprotein that suppresses matrix metalloprotease 9 (MMP-9), angiogenesis and epithelial cell motility. Here, we investigated the regulation and function of in epithelial ovarian cancer (EOC). FBLN5 mRNA was down-regulated 5-fold in EOC relative to benign ovary. Not surprisingly, mRNA and enzyme activity were increased significantly, and inversely correlated with gene expression. FBLN5 degradation products of 52.8 and 41.3 kDa were increased substantially in EOC. We identified two candidate proteases (serine elastase and MMP-7, but not MMP-9) that cleave FBLN5. MMP-7, but not neutrophil elastase, gene expression was increased dramatically in EOC. Recombinant FBLN5 significantly inhibited adhesion of EOC cells to both laminin and collagen I. Finally, using immunohistochemistry, we found immunoreactive FBLN5 within tumor macrophages throughout human EOC tumors. This work indicates that FBLN5 is degraded in EOC most likely by proteases enriched in macrophages of the tumor microenvironment. Proteolysis of FBLN5 serves as a mechanism to promote cell adhesion and local metastasis of ovarian cancer cells. Promotion of a stable ECM with intact FBLN5 in the tumor matrix may serve as a novel therapeutic adjunct to prevent spread of ovarian cancer.
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http://dx.doi.org/10.18632/oncotarget.24484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865667PMC
March 2018

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes.

Transl Lung Cancer Res 2018 Feb;7(1):32-49

Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.

Background: Small cell lung cancer (SCLC) is a deadly, high grade neuroendocrine (NE) tumor without recognized morphologic heterogeneity. However, over 30 years ago we described a SCLC subtype with "variant" morphology which did not express some NE markers and exhibited more aggressive growth.

Methods: To quantitate NE properties of SCLCs, we developed a 50-gene expression-based NE score that could be applied to human SCLC tumors and cell lines, and genetically engineered mouse (GEM) models. We identified high and low NE subtypes of SCLC in all of our sample types, and characterized their properties.

Results: We found that 16% of human SCLC tumors and 10% of SCLC cell lines were of the low NE subtype, as well as cell lines from the GEM model. High NE SCLC lines grew as non-adherent floating aggregates or spheroids while Low NE lines had morphologic features of the variant subtype and grew as loosely attached cells. While the high NE subtype expressed one of the NE lineage master transcription factors or , together with , the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST, the low NE subtype had lost expression of most NE markers, , and and expressed . The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene . Importantly, the high and low NE group of SCLC lines had similar gene expression profiles as their SCLC tumor counterparts.

Conclusions: SCLC tumors and cell lines can exhibit distinct inter-tumor heterogeneity with respect to expression of NE features. Loss of NE expression results in major alterations in morphology, growth characteristics, and molecular properties. These findings have major clinical implications as the two subtypes are predicted to have very different responses to targeted therapies.
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http://dx.doi.org/10.21037/tlcr.2018.02.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835590PMC
February 2018

Morphologic and Other Forms of Heterogeneity in Small Cell Lung Cancer: What Can We Learn from Them?

Authors:
Adi F Gazdar

J Thorac Oncol 2018 02;13(2):148-150

Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2017.11.004DOI Listing
February 2018

The Epithelial Sodium Channel (αENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors.

Transl Oncol 2018 Apr 2;11(2):292-299. Epub 2018 Feb 2.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/αENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects.
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http://dx.doi.org/10.1016/j.tranon.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884185PMC
April 2018

Small-cell lung cancer: what we know, what we need to know and the path forward.

Nat Rev Cancer 2017 Nov 10;17(12):765. Epub 2017 Nov 10.

This corrects the article DOI: 10.1038/nrc.2017.87.
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http://dx.doi.org/10.1038/nrc.2017.106DOI Listing
November 2017

Small-cell lung cancer: what we know, what we need to know and the path forward.

Nat Rev Cancer 2017 12 27;17(12):725-737. Epub 2017 Oct 27.

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75230-8593, USA.

Small-cell lung cancer (SCLC) is a deadly tumour accounting for approximately 15% of lung cancers and is pathologically, molecularly, biologically and clinically very different from other lung cancers. While the majority of tumours express a neuroendocrine programme (integrating neural and endocrine properties), an important subset of tumours have low or absent expression of this programme. The probable initiating molecular events are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling. SCLC, when diagnosed, is usually widely metastatic and initially responds to cytotoxic therapy but nearly always rapidly relapses with resistance to further therapies. There were no important therapeutic clinical advances for 30 years, leading SCLC to be designated a 'recalcitrant cancer'. Scientific studies are hampered by a lack of tissue availability. However, over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts. These studies have led to the discovery of new potential therapeutic vulnerabilities for SCLC and therefore to new clinical trials. Thus, while the past has been bleak, the future offers greater promise.
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http://dx.doi.org/10.1038/nrc.2017.87DOI Listing
December 2017

GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma.

Cancer Res 2017 08 26;77(16):4448-4459. Epub 2017 Jun 26.

Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here, we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559311PMC
August 2017

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors.

Cell Rep 2017 05;19(8):1669-1684

Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.
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http://dx.doi.org/10.1016/j.celrep.2017.04.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531293PMC
May 2017

Genome-wide copy number variation pattern analysis and a classification signature for non-small cell lung cancer.

Genes Chromosomes Cancer 2017 07 4;56(7):559-569. Epub 2017 May 4.

School of Chemical Engineering and Technology, Tianjin University, 300072 Tianjin, People's Republic of China.

The accurate classification of non-small cell lung carcinoma (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is essential for both clinical practice and lung cancer research. Although the standard WHO diagnosis of NSCLC on biopsy material is rapid and economic, more than 13% of NSCLC tumors in the USA are not further classified. The purpose of this study was to analyze the genome-wide pattern differences in copy number variations (CNVs) and to develop a CNV signature as an adjunct test for the routine histopathologic classification of NSCLCs. We investigated the genome-wide CNV differences between these two tumor types using three independent patient datasets. Approximately half of the genes examined exhibited significant differences between LUAD and LUSC tumors and the corresponding non-malignant tissues. A new classifier was developed to identify signature genes out of 20 000 genes. Thirty-three genes were identified as a CNV signature of NSCLC. Using only their CNV values, the classification model separated the LUADs from the LUSCs with an accuracy of 0.88 and 0.84, respectively, in the training and validation datasets. The same signature also classified NSCLC tumors from their corresponding non-malignant samples with an accuracy of 0.96 and 0.98, respectively. We also compared the CNV patterns of NSCLC tumors with those of histologically similar tumors arising at other sites, such as the breast, head, and neck, and four additional tumors. Of greater importance, the significant differences between these tumors may offer the possibility of identifying the origin of tumors whose origin is unknown.
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http://dx.doi.org/10.1002/gcc.22460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555588PMC
July 2017

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types.

Biochem Pharmacol 2017 08 2;137:1-9. Epub 2017 Apr 2.

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, United States.

At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsPKinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsPKinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsPKinase activity as well as actin bundling activity of ITPKA.
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http://dx.doi.org/10.1016/j.bcp.2017.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555585PMC
August 2017

Role of CPS1 in Cell Growth, Metabolism and Prognosis in LKB1-Inactivated Lung Adenocarcinoma.

J Natl Cancer Inst 2017 03;109(3):1-9

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Liver kinase B1 ( LKB1 ) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC.

Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided.

Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95% confidence interval = 1.74 to 5.25, P < .001).

Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.
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http://dx.doi.org/10.1093/jnci/djw231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198847PMC
March 2017

Characterization of Human Cancer Cell Lines by Reverse-phase Protein Arrays.

Cancer Cell 2017 02;31(2):225-239

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Cancer cell lines are major model systems for mechanistic investigation and drug development. However, protein expression data linked to high-quality DNA, RNA, and drug-screening data have not been available across a large number of cancer cell lines. Using reverse-phase protein arrays, we measured expression levels of ∼230 key cancer-related proteins in >650 independent cell lines, many of which have publically available genomic, transcriptomic, and drug-screening data. Our dataset recapitulates the effects of mutated pathways on protein expression observed in patient samples, and demonstrates that proteins and particularly phosphoproteins provide information for predicting drug sensitivity that is not available from the corresponding mRNAs. We also developed a user-friendly bioinformatic resource, MCLP, to help serve the biomedical research community.
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http://dx.doi.org/10.1016/j.ccell.2017.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501076PMC
February 2017

Proportion of Never-Smoker Non-Small Cell Lung Cancer Patients at Three Diverse Institutions.

J Natl Cancer Inst 2017 01 28;109(7). Epub 2017 Jan 28.

Affiliations of authors: Department of Internal Medicine, Hematology/Oncology, Harold C. Simmons Comprehensive Cancer Center (LP, AM, JDM, JS), Department of Biostatistics (CA, AG), Hamon Center for Therapeutic Oncology Research (JDM, AFG), Department of Pharmacology (JDM), Department of Pathology (AFG), UT Southwestern, Dallas, TX; Department of Hematology/Oncology, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Nashville, TN (LH, DM); Parkland Memorial Hospital, Dallas, TX (JC).

Background: Approximately 10% to 15% of lung cancer cases in the United States occur in never smokers, but there has been much debate about whether this rate is increasing. To determine whether the proportion of never smokers among lung cancer cases is increasing, we conducted a retrospective study using registries from The University of Texas Southwestern Medical Center, Parkland Hospital, and Vanderbilt University.

Methods: Registries were queried for demographic information from 1990 to 2013 including sex, age, stage, and self-reported smoking history. Ten thousand five hundred ninety-three non-small cell lung cancer (NSCLC) case patients and 1510 small cell lung cancer (SCLC) case patients were captured, and logistic regression analysis was performed. All statistical tests were two-sided.

Results: The proportion of never-smoker NSCLC patients increased from 8.0% in the years 1990 to 1995 to 14.9% in 2011 to 2013 (P < .001). This increase was also observed using multivariable logistic regression after controlling for sex, stage at diagnosis, and race/ethnicity. The percentage of never smokers among SCLC case patients (1.5% in 1990-1995 to 2.5% in 2011-2013, P = .36) or squamous cell NSCLC case patients did not statistically significantly change during this period.

Conclusions: This study demonstrates an increasing proportion of NSCLC patients who have never smoked in a large, diverse patient population between 1990 and 2013. Given that this increase appears independent of sex, stage, and race/ethnicity and also occurred in our county hospital, this trend is unlikely due to changes in referral patterns and suggests that the actual incidence of lung cancer in never smokers is increasing.
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http://dx.doi.org/10.1093/jnci/djw295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279285PMC
January 2017

SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers.

Nat Commun 2017 01 19;8:14098. Epub 2017 Jan 19.

Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.

Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.
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http://dx.doi.org/10.1038/ncomms14098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253647PMC
January 2017

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition.

Cancer Cell 2017 02 12;31(2):270-285. Epub 2017 Jan 12.

Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA. Electronic address:

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.
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http://dx.doi.org/10.1016/j.ccell.2016.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310991PMC
February 2017

SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II-III Diffuse Gliomas.

EBioMedicine 2016 Nov 28;13:80-89. Epub 2016 Oct 28.

The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Background: Diffuse gliomas, grades II and III, hereafter called lower-grade gliomas (LGG), have variable, difficult to predict clinical courses, resulting in multiple studies to identify prognostic biomarkers. The purpose of this study was to assess expression or methylation of the homeobox family gene SHOX2 as independent markers for LGG survival.

Methods: We downloaded publically available glioma datasets for gene expression and methylation. The Cancer Genome Atlas (TCGA) (LGG, n=516) was used as a training set, and three other expression datasets (n=308) and three other methylation datasets (n=320), were used for validation. We performed Kaplan-Meier survival curves and univariate and multivariate Cox regression model analyses.

Findings: SHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival. While they were tightly correlated, SHOX2 expression appeared more potent as a prognostic marker and was used for most further studies. The SHOX2 prognostic roles were maintained after analyses by histology subtypes or tumor grade. We found that the combination of SHOX2 expression and IDH genotype status identified a subset of LGG patients with IDH wild-type (IDHwt) and low SHOX2 expression with considerably favorable survival. We further investigated the combination of SHOX2 with other known clinically relevant markers of LGG (TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of LGG patients with significantly favorable survival outcomes, especially in the subgroup with worse prognosis for each individual marker. Finally, multivariate analysis demonstrated that SHOX2 was a potent independent survival marker.

Interpretation: We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. The combination of IDH or other relevant markers with SHOX2 identified LGG subsets with significantly different survival outcomes, and further understanding of these subsets may benefit therapeutic target identification and therapy selections for glioma patients.
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http://dx.doi.org/10.1016/j.ebiom.2016.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264450PMC
November 2016

ZEB1 drives epithelial-to-mesenchymal transition in lung cancer.

J Clin Invest 2016 09 8;126(9):3219-35. Epub 2016 Aug 8.

Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-β) or oncogenetic (MYC) factors. Both TGF-β- and MYC-induced EMT required ZEB1, but engaged distinct TGF-β-dependent and vitamin D receptor-dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non-small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-β and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.
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http://dx.doi.org/10.1172/JCI76725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004933PMC
September 2016
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