Rosana Eisenberg

Vanderbilt University Medical Center

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Pierre P. Massion

Vanderbilt University Medical Center

Heidi Chen

Vanderbilt University Medical Center

Megan D. Hoeksema

Pierian Biosciences (United States)

Masakazu Shiota

Vanderbilt University

Mohamed Hassanein

Dubai Hospital

Jun Qian

Zhejiang University

Bradford K. Harris

Vanderbilt University

S.M. Jamshedur Rahman

University of Cambridge

Jonathan E. Clark

Florida A&M University - Florida State University College of Engineering

Fredrick T. Harris

Meharry Medical College

Cooperative Institutions

Vanderbilt University Medical Center

129

Vanderbilt University

129

Tumori Foundation

Memorial Sloan Kettering Cancer Center

Vanderbilt-Ingram Cancer Center

The University of Texas MD Anderson Cancer Center

Case Western Reserve University

Johns Hopkins University

National Cancer Institute

Cornell University

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Data from SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival

Mohamed Hassanein Megan D. Hoeksema Masakazu Shiota Jun Qian Bradford K. Harris

<div>AbstractPurpose: We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non–small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival.Experimental Design: To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines.Results: Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na+-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling.Conclusions: These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival. Clin Cancer Res; 19(3); 560–70. ©2012 AACR.</div>

10.1158/1078-0432.c.6522227

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Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma

Journal of Proteome Research (2017)

Simona G. Codreanu Megan D. Hoeksema Robbert J.C. Slebos Lisa J. Zimmerman S.M. Jamshedur Rahman

We hypothesized that distinct protein expression features of benign and malignant pulmonary nodules may reveal novel candidate biomarkers for the early detection of lung cancer. We performed proteome profiling by liquid chromatography-tandem mass spectrometry to characterize 34 resected benign lung nodules, 24 untreated lung adenocarcinomas (ADCs), and biopsies of bronchial epithelium. Group comparisons identified 65 proteins that differentiate nodules from ADCs and normal bronchial epithelium and 66 proteins that differentiate ADCs from nodules and normal bronchial epithelium. We developed a multiplexed parallel reaction monitoring (PRM) assay to quantify a subset of 43 of these candidate biomarkers in an independent cohort of 20 benign nodules, 21 ADCs, and 20 normal bronchial biopsies. PRM analyses confirmed significant nodule-specific abundance of 10 proteins including ALOX5, ALOX5AP, CCL19, CILP1, COL5A2, ITGB2, ITGAX, PTPRE, S100A12, and SLC2A3 and significant ADC-specific abundance of CEACAM6, CRABP2, LAD1, PLOD2, and TMEM110-MUSTN1. Immunohistochemistry analyses for seven selected proteins performed on an independent set of tissue microarrays confirmed nodule-specific expression of ALOX5, ALOX5AP, ITGAX, and SLC2A3 and cancer-specific expression of CEACAM6. These studies illustrate the value of global and targeted proteomics in a systematic process to identify and qualify candidate biomarkers for noninvasive molecular diagnosis of lung cancer.

Tissue microarray

Nodule (geology)

10.1021/acs.jproteome.7b00245

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Supplementary Methods from SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival

Mohamed Hassanein Megan D. Hoeksema Masakazu Shiota Jun Qian Bradford K. Harris

PDF file - 164K

10.1158/1078-0432.22451585.v1

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Author Reply: In Response to “De Novo KRAS G12C-Mutant SCLC: A Case Report”

JTO Clinical and Research Reports (2022)

Meridith L. Balbach Rosana Eisenberg Wade T. Iams

We thank Moore et al.1 for their thoughtful consideration of our patient case with de novo KRAS G12C-mutant SCLC. We agree that the variant allele frequency, although quite high in this patient, does not ensure the importance of this mutation in driving the patient’s SCLC. In the era of ever-increasing breadth and depth of tumor genomic profiling, a plentitude of patients with “targetable” mutations in noncanonical settings continue to present challenges and opportunities akin to this case. The ability to reliably estimate the cancer effect size of individual mutations is a tool of immense value to molecular tumor board discussions, clinical trial design, and practicing oncologists.

10.1016/j.jtocrr.2022.100425

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Activation state egfr and STAT-3 as prognostic markers in resected non-small cell lung cancer

Lung Cancer (2006)

Tania Cortas Rosana Eisenberg Pingfu Fu Jeffrey A. Kern Lauren Patrick

10.1016/j.lungcan.2006.11.003

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Evidence for Common Clonal Origin of Multifocal Lung Cancers

JNCI Journal of the National Cancer Institute (2009)

Xiaoyan Wang Ming‐Sheng Wang Gregory T. MacLennan Fadi W. Abdul‐Karim John N. Eble

Lung cancer is the most common cause of cancer death in the United States. Multiple anatomically separate but histologically similar lung tumors are often found in the same patient. The clonal origin of multiple lung tumors is uncertain.We analyzed 70 lung tumors from 30 patients (23 females and seven males) who underwent surgical resection for lung epithelial tumors, of whom 26 had non-small cell carcinomas and four had carcinoid/atypical carcinoid tumors. All patients had multiple tumors (two to five) involving one or both lungs. Genomic DNA was extracted from paraffin-embedded tissue sections using laser capture microdissection and analyzed for loss of heterozygosity, TP53 mutations, and X-chromosome inactivation status. The percentage (95% confidence interval [CI]) of patients in whom there were concordant patterns of genetic alteration was calculated.All 30 case subjects showed loss of heterozygosity (LOH) in at least one and at most four of the six polymorphic microsatellite markers. Completely concordant LOH patterns between synchronous and metachronous cancers in individual patients were seen in 26 (87%) of 30 informative patients (95% CI = 75% to 99%). Identical point mutations were present in eight of 10 patients who exhibited TP53 mutation by sequencing. Tumors in 18 (78%) of 23 female patients (95% CI = 67% to 98%) showed identical X-chromosome inactivation patterns. Combining the results of LOH studies, TP53 mutation screening analyses, and X-chromosome inactivation data, we demonstrated that the multiple separate tumors in 23 (77%) of 30 patients (95% CI = 62% to 92%) had identical genetic changes, consistent with monoclonal origin of the separate tumors.Our data indicate that the great majority of multifocal lung cancers have a common clonal origin and that multifocality in lung cancer represents local and regional intrapulmonary metastasis.

Microdissection

10.1093/jnci/djp054

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Supplementary Figure 3 from Acyl-Coenzyme A–Binding Protein Regulates Beta-Oxidation Required for Growth and Survival of Non–Small Cell Lung Cancer

Fredrick T. Harris S.M. Jamshedur Rahman Mohamed Hassanein Jun Qian Megan D. Hoeksema

PDF file - 129KB, Supplemental Figure 3. ACBP downregulation decreases proliferation and induces apoptosis in A549 NSCLC cells.

BETA (programming language)

Coenzyme A

10.1158/1940-6207.22525197.v1

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Supplementary Table 1 from Acyl-Coenzyme A–Binding Protein Regulates Beta-Oxidation Required for Growth and Survival of Non–Small Cell Lung Cancer

Fredrick T. Harris S.M. Jamshedur Rahman Mohamed Hassanein Jun Qian Megan D. Hoeksema

PDF file - 68KB, Supplemental Table 1. Clinical correlates of microarray data sets.

BETA (programming language)

Coenzyme A

10.1158/1940-6207.22525188.v1

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xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression

Oncogene (2018)

Xiangming Ji Jun Qian S.M. Jamshedur Rahman Peter J. Siska Yong Zou

Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC.

Tumor progression

Reprogramming

10.1038/s41388-018-0307-z

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Citations (277)

Regulatory thresholds for xylazine – review and analysis based on recent pharmacokinetic data

Pferdeheilkunde Equine Medicine (2024)

L E Macomber Glenys Noble Kimberly Brewer Abelardo Morales Briceño Maria A. O’Connell

10.21836/pem20240306

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