Molecular Portraits of Epithelial, Mesenchymal, and Hybrid States in Lung Adenocarcinoma and Their Relevance to Survival

Schliekelman, Mark J.; Taguchi, Ayumu; Zhu, Jun; Dai, Xudong; Rodríguez, Jaime; Çeliktaş, Müge; Zhang, Qing; Chin, Alice; Wong, Chee-Hong; Wang, Hong; McFerrin, Lisa; Selamat, Suhaida A.; Yang, Chengli; Kroh, Evan M.; Garg, Kavita S.; Behrens, Carmen; Gazdar, Adi F.; Laird-Offringa, Ite A.; Tewari, Muneesh; Wistuba, Ignacio I.; Thiery, Jean Paul; Hanash, Samir M.

doi:10.1158/0008-5472.can-14-2535

Cited by 194 publications

(183 citation statements)

References 49 publications

(38 reference statements)

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“…Three cell lines with indeterminate LKB1 status were excluded from further analysis. LKB1 inactivation status was statistically significantly associated with epidermal growth factor receptor (EGFR) and KRAS mutational status (P ¼ .01, chi-square test), supporting previous studies (6), but was not statistically significant related to phenotypic characteristics such as cell morphology or invasion properties (data not shown) (23).…”

Section: Comparison Of Proteomic Profiling Of Lkb1-inactivated and -Isupporting

confidence: 85%

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

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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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 ratelimiting 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 ¼ 3.03, 95% confidence interval ¼ 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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Section: Comparison Of Proteomic Profiling Of Lkb1-inactivated and -Isupporting

confidence: 85%

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

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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“…Loss of APC/C results in cell cycle arrest at metaphase and severe aberrations of the mitotic spindle (23). To further investigate the relationship between KPNB1 and APC/C protein levels, we analyzed liquid chromatography (LC)-MS data for various other human cancer cell lines (24). We observed a positive correlation in protein levels between KPNB1 and multiple APC/C family members in several different cancer types (Fig.…”

Section: Kpnb1 Positively Regulates Members Of the Anaphase-promotingmentioning

confidence: 92%

“…For the IP-MS experiment, nuclear cell extracts of SKOV3 were obtained as described above and immunoprecipitated by IgG or KPNB1 antibody (Abcam). MS analysis were performed as previously described (24). Bioinformatic Analysis.…”

Section: Methodsmentioning

confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/ C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.ovarian cancer | KPNB1 | loss-of-function screen | CRISPR/Cas | RNAi

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“…13 C]lysine and 10% (vol/vol) dialyzed FBS according to the standard protocol (47). Details are given in SI Appendix, Section 4.…”

Section: Methodsmentioning

confidence: 99%

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Tripathi

Peters

Taguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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182

175

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The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.

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Molecular Portraits of Epithelial, Mesenchymal, and Hybrid States in Lung Adenocarcinoma and Their Relevance to Survival

Cited by 194 publications

References 49 publications

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

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

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

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