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1.
Jieun Lee Ahyoung Choi SungYup Cho Yukyung Jun Deukchae Na Ahra Lee Giyong Jang Jee Young Kwon Jaesang Kim Sanghyuk Lee Charles Lee 《Molecular oncology》2021,15(2):487
Erlotinib is highly effective in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, despite initial favorable responses, most patients rapidly develop resistance to erlotinib soon after the initial treatment. This study aims to identify new genes and pathways associated with erlotinib resistance mechanisms in order to develop novel therapeutic strategies. Here, we induced knockout (KO) mutations in erlotinib‐resistant human lung cancer cells (NCI‐H820) using a genome‐scale CRISPR‐Cas9 sgRNA library to screen for genes involved in erlotinib susceptibility. The spectrum of sgRNAs incorporated among erlotinib‐treated cells was substantially different to that of the untreated cells. Gene set analyses showed a significant depletion of ‘cell cycle process’ and ‘protein ubiquitination pathway’ genes among erlotinib‐treated cells. Chemical inhibitors targeting genes in these two pathways, such as nutlin‐3 and carfilzomib, increased cancer cell death when combined with erlotinib in both in vitro cell line and in vivo patient‐derived xenograft experiments. Therefore, we propose that targeting cell cycle processes or protein ubiquitination pathways are promising treatment strategies for overcoming resistance to EGFR inhibitors in lung cancer.
Abbreviations
- ATCC
- American Type Culture Collection
- edgeR
- bioconductor software package for examining differential expression of replicated count data
- EGFR
- epidermal growth factor receptor
- GeCKO
- genome‐scale CRISPR/Cas9 knockout
- HGF
- hepatocyte growth factor
- MAGeCK‐VISPR algorithm
- comprehensive quality control analysis and visualization pipeline for CRISPR/Cas9 screens based on MAGeCK VISPR
- MOI
- multiplicity of infection
- NSCLC
- non‐small‐cell lung cancer
- SCLC
- small cell lung cancer
- sgRNA
- single‐guide RNA
- TKIs
- tyrosine kinase inhibitors
2.
3.
Abril Marcela HerreraSolorio Irlanda PeraltaArrieta Leonel Armas Lpez Nallely HernndezCigala Criselda Mendoza Milla Blanca Ortiz Quintero Rodrigo Cataln Crdenas Priscila Pineda Villegas Evelyn Rodríguez Villanueva Cynthia G. Trejo Iriarte Joaquín Zúiga Oscar Arrieta Federico vilaMoreno 《Molecular oncology》2021,15(4):1110
4.
《Molecular oncology》2021,15(1):43
Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.
Abbreviations
- BEAMing
- beads, emulsion, amplification, and magnetics
- cfDNA
- circulating free DNA, cell‐free DNA
- cobas
- cobas® EGFR Mutation Test v2 (Roche Diagnostics)
- ctDNA
- circulating tumor DNA
- CUSUM
- cumulative sum
- ddPCR
- droplet digital polymerase chain reaction
- dPCR
- digital polymerase chain reaction
- EGFR
- epidermal growth factor receptor
- FFPE
- formalin‐fixed, paraffin‐embedded
- ICC
- intraclass correlation coefficient
- MAF
- mutant allele frequency
- NGS platforms
- Ion S5™ XL and GeneRead™
- NGS
- next‐generation sequencing
- NSCLC
- non‐small‐cell lung cancer
- PNA‐Q‐PCR
- peptic nucleic acid probe‐based real‐time polymerase chain reaction
- Therascreen
- Therascreen EGFR Plasma RGQ PCR Kit (QIAgen)
- TKI
- tyrosine kinase inhibitor
5.
6.
《Molecular oncology》2021,15(5):1412
The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Abbreviations
- 7‐AAD
- 7‐Aminoactinomycin D
- BPTES
- bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl)ethyl sulfide
- DON
- diazo‐5‐oxo‐L‐norleucine
- ECAR
- extracellular acidification rate
- GDH
- glutamate dehydrogenase
- GLS
- glutaminase
- GS
- glutamine synthetase
- GSI
- γ‐secretase inhibitor
- MSO
- L‐methionine sulfoximine
- mTORC1
- mammalian target of rapamycin complex 1
- NICD
- Notch intracellular domain
- PI
- propidium iodide
- RAP
- rapamycin
- T‐ALL
- T‐cell acute lymphoblastic leukemia
- TCA
- tricarboxylic acid
- αKG
- α‐ketoglutarate
7.
Joan Frigola Alejandro Navarro Caterina Carbonell Ana Callejo Patricia Iranzo Susana Cedrs Alex MartinezMarti Nuria Pardo Nadia SaoudiGonzalez Debora Martinez Jose Jimenez Irene Sansano Francesco M. Mancuso Paolo Nuciforo Luis M. Montuenga Montse SnchezCespedes Aleix Prat Ana Vivancos Enriqueta Felip Ramon Amat 《Molecular oncology》2021,15(4):887
8.
Debora Bencivenga Emanuela Stampone Arianna Aulitto Annunziata Tramontano Clementina Barone Aide Negri Domenico Roberti Silverio Perrotta Fulvio Della Ragione Adriana Borriello 《Molecular oncology》2021,15(4):915
CDKN1B haploinsufficiency promotes the development of several human cancers. The gene encodes p27Kip1, a protein playing pivotal roles in the control of growth, differentiation, cytoskeleton dynamics, and cytokinesis. CDKN1B haploinsufficiency has been associated with chromosomal or gene aberrations. However, very few data exist on the mechanisms by which CDKN1B missense mutations facilitate carcinogenesis. Here, we report a functional study on a cancer‐associated germinal p27Kip1 variant, namely glycine9‐>arginine‐p27Kip1 (G9R‐p27Kip1) identified in a parathyroid adenoma. We unexpectedly found that G9R‐p27Kip1 lacks the major tumor suppressor activities of p27Kip1 including its antiproliferative and pro‐apoptotic functions. In addition, G9R‐p27Kip1 transfection in cell lines induces the formation of more numerous and larger spheres when compared to wild‐type p27Kip1‐transfected cells. We demonstrated that the mutation creates a consensus sequence for basophilic kinases causing a massive phosphorylation of G9R‐p27Kip1 on S12, a residue normally never found modified in p27Kip1. The novel S12 phosphorylation appears responsible for the loss of function of G9R‐p27Kip1 since S12AG9R‐p27Kip1 recovers most of the p27Kip1 tumor suppressor activities. In addition, the expression of the phosphomimetic S12D‐p27Kip1 recapitulates G9R‐p27Kip1 properties. Mechanistically, S12 phosphorylation enhances the nuclear localization of the mutant protein and also reduces its cyclin‐dependent kinase (CDK)2/CDK1 inhibition activity. To our knowledge, this is the first reported case of quantitative phosphorylation of a p27Kip1 variant on a physiologically unmodified residue associated with the loss of several tumor suppressor activities. In addition, our findings demonstrate that haploinsufficiency might be due to unpredictable post‐translational modifications due to generation of novel consensus sequences by cancer‐associated missense mutations.
Abbreviations
- 1D/WB
- monodimensional western blotting
- 2D/WB
- two‐dimensional western blotting
- CDK
- cyclin‐dependent kinase
- CHX
- cycloheximide
- G9R‐p27
- glycine9‐>arginine‐p27
- IUPs
- intrinsically unstructured proteins
- mAbs
- monoclonal antibodies
- MEN
- multiple endocrine neoplasia
- MENX
- multiple endocrine neoplasia X
- PTMs
- post‐translational modifications
- rAbs
- rabbit antibodies
- TSG
- tumor suppressor gene
- wt‐p27
- wild‐type p27
9.
Danmei Zhou Kehan Ren Meili Wang Jigang Wang Ermin Li Chenjian Hou Ying Su Yiting Jin Qiang Zou Ping Zhou Xiuping Liu 《Molecular oncology》2021,15(2):543
Long non‐coding RNAs (lncRNAs) are emerging as key molecules in various cancers, yet their potential roles in the pathogenesis of breast cancer are not fully understood. Herein, using microarray analysis, we revealed that the lncRNA RACGAP1P, the pseudogene of Rac GTPase activating protein 1 (RACGAP1), was up‐regulated in breast cancer tissues. Its high expression was confirmed in 25 pairs of breast cancer tissues and 8 breast cell lines by qRT‐PCR. Subsequently, we found that RACGAP1P expression was positively correlated with lymph node metastasis, distant metastasis, TNM stage, and shorter survival time in 102 breast cancer patients. Then, in vitro and in vivo experiments were designed to investigate the biological function and regulatory mechanism of RACGAP1P in breast cancer cell lines. Overexpression of RACGAP1P in MDA‐MB‐231 and MCF7 breast cell lines increased their invasive ability and enhanced their mitochondrial fission. Conversely, inhibition of mitochondrial fission by Mdivi‐1 could reduce the invasive ability of RACGAP1P‐overexpressing cell lines. Furthermore, the promotion of mitochondrial fission by RACGAP1P depended on its competitive binding with miR‐345‐5p against its parental gene RACGAP1, leading to the activation of dynamin‐related protein 1 (Drp1). In conclusion, lncRNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1 pathway‐mediated mitochondrial fission.
Abbreviations
- CDS
- coding sequence
- ceRNAs
- competitive endogenous RNAs
- Drp1
- dynamin‐related protein 1
- FFPE
- formalin‐fixed paraffin‐embedded
- lncRNAs
- long non‐coding RNAs
- miRNAs
- microRNAs
- RACGAP1
- Rac GTPase activating protein 1
- TCGA
- The Cancer Genome Atlas
10.
Kazuko Sakai Takayuki Takahama Mototsugu Shimokawa Koichi Azuma Masayuki Takeda Terufumi Kato Haruko Daga Isamu Okamoto Hiroaki Akamatsu Shunsuke Teraoka Akira Ono Tatsuo Ohira Toshihide Yokoyama Nobuyuki Yamamoto Kazuhiko Nakagawa Kazuto Nishio 《Molecular oncology》2021,15(1):126
The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
Abbreviations
- CIs
- confidence intervals
- ctDNA
- circulating tumor DNA
- ddPCR
- droplet digital PCR
- EGFR
- epidermal growth factor receptor
- MFs
- mutant fractions
- NGS
- next‐generation sequencing
- NSCLC
- non‐small cell lung cancer
- ORR
- overall response rate
- OS
- overall survival
- PD
- progressive disease
- PFS
- progression‐free survival
- PR
- partial response
- SD
- stable disease
- TKI
- tyrosine kinase inhibitor
11.
Xin Guo Aman Wang Wen Wang Ya Wang Huan Chen Xiaolong Liu Tian Xia Aijia Zhang Di Chen Huan Qi Ting Ling Hailong Piao Hongjiang Wang 《Molecular oncology》2021,15(2):642
Dependence on glutamine and acceleration of fatty acid oxidation (FAO) are both metabolic characteristics of triple‐negative breast cancer (TNBC). With the rapid growth of tumors, accelerated glutamine catabolism depletes local glutamine, resulting in glutamine deficiency. Studies have shown that the use of alternative energy sources, such as fatty acids, enables tumor cells to continue to proliferate rapidly in a glutamine‐deficient microenvironment. However, the detailed mechanisms behind this metabolic change are still unclear. Herein, we identified HRD1 as a regulatory protein for FAO that specifically inhibits TNBC cell proliferation under glutamine‐deficient conditions. Furthermore, we observed that HRD1 expression is significantly downregulated under glutamine deprivation and HRD1 directly ubiquitinates and stabilizes CPT2 through K48‐linked ubiquitination. In addition, the inhibition of CPT2 expression dramatically suppresses TNBC cell proliferation mediated by HRD1 knockdown in vitro and in vivo. Finally, we found that the glutaminase inhibitor CB839 significantly inhibited TNBC cell tumor growth, but not in the HRD1 knock‐downed TNBC cells. These findings provide an invaluable insight into HRD1 as a regulator of lipid metabolism and have important implications for TNBC therapeutic targeting.
Abbreviations
- CPT1A
- carnitine palmitoyltransferase 1A
- CPT2
- carnitine palmitoyltransferase 2
- FAO
- fatty acid oxidation
- GLS
- glutaminase
- HRD1
- HMG‐CoA reductase degradation protein 1
- LC‐MS
- liquid chromatography mass spectrometry
- TNBC
- triple‐negative breast cancer
12.
JeongYun Choi Haeseung Lee EunJi Kwon HyeonJoon Kong OkSeon Kwon HyukJin Cha 《Molecular oncology》2021,15(2):679
The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.
Abbreviations
- AUC
- area under the curve
- AXL
- AXL receptor tyrosine kinase
- BCL2
- B‐cell lymphoma 2
- CTD2
- cancer target discovery and development
- CTGF
- connective tissue growth factor
- DEG
- differentially expressed genes
- DOXO
- doxorubicin
- EMT
- epithelial–mesenchymal transition
- Eto
- etoposide
- FDA
- Food and Drug Administration
- ITGB3
- integrin beta‐3
- MAPK
- mitogen‐activated protein kinase
- MMP2
- matrix metalloproteinase‐2
- MMP9
- matrix metalloproteinase‐9
- mRNA
- messenger RNA
- NF‐κB
- nuclear factor kappa‐light‐chain‐enhancer of activated B cells
- SBE
- SMAD binding element
- SERPINE1
- serpin family E member 1
- siRNA
- small interfering RNA
- ssGSEA
- single‐sample gene set enrichment analysis
- TCGA
- The Cancer Genome Atlas
- TGFβ
- transforming growth factor beta
- YAP
- Yes‐associated protein
- YAP8SA
- mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP
- ZEB1
- zinc finger E‐box binding homeobox 1
- ZEB2
- zinc finger E‐box‐binding homeobox 2
13.
Evelina Miele Agnese Po Angela Mastronuzzi Andrea Carai Zein Mersini Besharat Natalia Pediconi Luana Abballe Giuseppina Catanzaro Claudia Sabato Enrico De Smaele Gianluca Canettieri Lucia Di Marcotullio Alessandra Vacca Antonello Mai Massimo Levrero Stefan M. Pfister Marcel Kool Felice Giangaspero Franco Locatelli Elisabetta Ferretti 《Molecular oncology》2021,15(2):523
Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR‐326 and its host gene β‐arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro‐survival function. Our models revealed that miR‐326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation‐associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR‐326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR‐326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro‐apoptotic activity. Similar to miR‐326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR‐326/ARRB1 expression, limiting E2F1 pro‐proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
Abbreviations
- ARRB1
- β‐arrestin1
- BTC
- bulk tumor cell
- CSCs
- cancer stem cells
- EZH2
- enhancer of zeste homolog 2
- GCP
- granule cell progenitors
- MB
- medulloblastoma
- OFC
- oncosphere‐forming cell
14.
15.
Jia Liu Yang Zhan Jiefu Wang Junfeng Wang Jiansheng Guo Dalu Kong 《Molecular oncology》2020,14(12):3211
Metastasis accounts for poor prognosis of cancers and related deaths. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play critical roles in several types of cancer. However, which lncRNAs contribute to metastasis of colon cancer is still largely unknown. In this study, we found that lncRNA LINC01578 was correlated with metastasis and poor prognosis of colon cancer. LINC01578 was upregulated in colon cancer, associated with metastasis, advanced clinical stages, poor overall survival, disease‐specific survival, and disease‐free survival. Gain‐of‐function and loss‐of‐function assays revealed that LINC01578 enhanced colon cancer cell viability and mobility in vitro and colon cancer liver metastasis in vivo. Mechanistically, nuclear factor kappa B (NF‐κB) and Yin Yang 1 (YY1) directly bound to the LINC01578 promoter, enhanced its activity, and activated LINC01578 expression. LINC01578 was shown to be a chromatin‐bound lncRNA, which directly bound NFKBIB promoter. Furthermore, LINC01578 interacted with and recruited EZH2 to NFKBIB promoter and further repressed NFKBIB expression, thereby activating NF‐κB signaling. Through activation of NF‐κB, LINC01578 further upregulated YY1 expression. Through activation of the NF‐κB/YY1 axis, LINC01578 in turn enhanced its own promoter activity, suggesting that LINC01578 and NF‐κB/YY1 formed a positive feedback loop. Blocking NF‐κB signaling abolished the oncogenic roles of LINC01578 in colon cancer. Furthermore, the expression levels of LINC01578, NFKBIB, and YY1 were correlated in clinical tissues. Collectively, this study demonstrated that LINC01578 promoted colon cancer metastasis via forming a positive feedback loop with NF‐κB/YY1 and suggested that LINC01578 represents a potential prognostic biomarker and therapeutic target for colon cancer metastasis.
Abbreviations
- ChIP
- chromatin immunoprecipitation
- ChIRP
- chromatin isolation by RNA purification
- COAD
- colon adenocarcinoma
- CPAT
- Coding‐Potential Assessment Tool
- CPC
- coding potential calculator
- DFS
- disease‐free survival
- DSS
- disease‐specific survival
- EdU
- 5‐ethynyl‐2''‐deoxyuridine
- H&E
- hematoxylin and eosin
- HR
- hazard ratio
- IHC
- immunohistochemistry
- IKK
- IκB kinase
- IκB
- inhibitory κB
- lncRNAs
- long noncoding RNAs
- NC
- negative control
- NCBI
- National Center for Biotechnology Information
- NF‐κB
- nuclear factor kappa B
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- RIP
- RNA immunoprecipitation
- RPISeq
- RNA‐Protein Interaction Prediction
- TCGA
- The Cancer Genome Atlas
- TNF
- tumor necrosis factor
- TUNEL
- TdT‐mediated dUTP Nick‐End Labeling
- YY1
- Yin Yang 1
16.
Esther Coronado Yania Yaez Enrique Vidal Luis Rubio Francisco VeraSempere Antonio Jos CaadaMartínez Joaquín Panadero Adela Caete Ruth Ladenstein Victoria Castel Jaime Font de Mora 《Molecular oncology》2021,15(2):364
High‐risk neuroblastoma (NB) patients with 11q deletion frequently undergo late but consecutive relapse cycles with fatal outcome. To date, no actionable targets to improve current multimodal treatment have been identified. We analyzed immune microenvironment and genetic profiles of high‐risk NB correlating with 11q immune status. We show in two independent cohorts that 11q‐deleted NB exhibits various immune inhibitory mechanisms, including increased CD4+ resting T cells and M2 macrophages, higher expression of programmed death‐ligand 1, interleukin‐10, transforming growth factor‐beta‐1, and indoleamine 2,3‐dioxygenase 1 (P < 0.05), and also higher chromosomal breakages (P ≤ 0.02) and hemizygosity of immunosuppressive miRNAs than MYCN‐amplified and other 11q‐nondeleted high‐risk NB. We also analyzed benefits of maintenance treatment in 83 high‐risk stage M NB patients focusing on 11q status, either with standard anti‐GD2 immunotherapy (n = 50) or previous retinoic acid‐based therapy alone (n = 33). Immunotherapy associated with higher EFS (50 vs. 30, P = 0.028) and OS (72 vs. 52, P = 0.047) at 3 years in the overall population. Despite benefits from standard anti‐GD2 immunotherapy in high‐risk NB patients, those with 11q deletion still face poor outcome. This NB subgroup displays intratumoral immune suppression profiles, revealing a potential therapeutic strategy with combination immunotherapy to circumvent this immune checkpoint blockade.
Abbreviations
- 11q‐del
- 11q‐deleted
- ADCC
- antibody‐dependent cellular cytotoxicity
- CDC
- complement‐dependent cytotoxicity
- COJEC
- chemotherapeutic agents cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
- CTLA‐4
- cytotoxic T lymphocyte antigen 4
- EFS
- event‐free survival
- FISH
- fluorescence in situ hybridization
- HR
- hazard ratio
- ICI
- immune checkpoint inhibitor
- IDO1
- indoleamine 2,3‐dioxygenase 1
- IFN‐γ
- interferon‐γ
- IL‐10
- interleukin 10
- INRG
- International Neuroblastoma Risk Group
- miR
- microRNA
- MLPA
- multiplex ligation‐dependent probe amplification
- MMR
- mismatch repair
- MNA
- MYCN amplification
- MS
- metastatic special stage
- MSI
- microsatellite instability
- NB
- neuroblastoma
- NCA
- numerical chromosome aberrations
- NOS
- nitric oxide synthase
- OS
- overall survival
- PD‐1
- programmed cell death protein 1
- PD‐L1
- programmed death‐ligand 1
- SCA
- segmental chromosome aberrations
- TAM
- tumor‐associated macrophages
- Tfh
- follicular helper T cells
- TGF‐β
- tumor growth factor‐β
- TMB
- tumor mutational burden
- TME
- tumor microenvironment
- TNF‐α
- tumor necrosis factor‐α
- Treg
- regulatory T cells
17.
Liang Liu Tamjeed Ahmed William J. Petty Stefan Grant Jimmy Ruiz Thomas W. Lycan Umit Topaloglu PingChieh Chou Lance D. Miller Gregory A. Hawkins Martha A. AlexanderMiller Stacey S. ONeill Bayard L. Powell Ralph B. DAgostino Jr. Reginald F. Munden Boris Pasche Wei Zhang 《Molecular oncology》2021,15(2):462
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin‐remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS‐mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK‐IMPACT Clinical Sequencing (MSK‐CT) cohorts; and KRAS‐mutant patients with LUAD who received immune checkpoint inhibitor‐based immunotherapy treatment from (c) the MSK‐IMPACT (MSK‐IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS‐mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e‐04 for disease‐free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS‐TP53 comutant (KP) and KRAS‐only mutant (K) patients; in the MSK‐CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression‐free survival (PFS; P = 0.0091) in the MSK‐IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.
Abbreviations
- DCB
- durable clinical benefit
- DFS
- disease‐free survival
- K
- KRAS‐only mutant
- KL
- KRAS‐STK11 comutant
- KP
- KRAS‐TP53 comutant
- KS
- KRAS‐SMARCA4 comutant
- LUAD
- lung adenocarcinoma
- LUSC
- lung squamous carcinoma
- MSK‐CT
- the MSK‐IMPACT clinical sequencing cohort
- MSK‐IO
- MSK‐IMPACT cohort
- NSCLC
- non‐small‐cell lung cancer
- OS
- overall survival
- PFS
- progression‐free survival
- TCGA
- The Cancer Genome Atlas
- WFBCCC
- the Wake Forest Baptist Comprehensive Cancer Center
18.
The oncogenic fusion protein nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK), found in anaplastic large‐cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM‐ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM‐ALK interacted with Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM‐ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0/G1‐phase cell cycle arrest in Ba/F3 cells transformed by NPM‐ALK and ALCL patient‐derived Ki‐JK cells, but not ALCL patient‐derived SUDH‐L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM‐ALK and Ki‐JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC‐0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt‐mTORC1 pathway in NPM‐ALK‐positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
Abbreviations
- ALCL
- anaplastic large‐cell lymphoma
- EBP2
- EBNA1‐binding protein 2
- IMT
- inflammatory myofibroblastic tumors
- mTOR
- mechanistic target of rapamycin
- mTORC1
- mTOR complex 1
- NoLS
- nucleolar localization signal
- NPM1
- nucleophosmin 1
- NPM‐ALK
- nucleophosmin‐anaplastic lymphoma kinase
- NSCLC
- non‐small cell lung cancer
- TPM3
- tropomyosin 3
19.
20.
Leptin, a hormone predominantly derived from adipose tissue, is well known to induce growth of breast cancer cells. However, its underlying mechanisms remain unclear. In this study, we examined the role of reprogramming of lipid metabolism and autophagy in leptin‐induced growth of breast cancer cells. Herein, leptin induced significant increase in fatty acid oxidation‐dependent ATP production in estrogen receptor‐positive breast cancer cells. Furthermore, leptin induced both free fatty acid release and intracellular lipid accumulation, indicating a multifaceted effect of leptin in fatty acid metabolism. These findings were further validated in an MCF‐7 tumor xenograft mouse model. Importantly, all the aforementioned metabolic effects of leptin were mediated via autophagy activation. In addition, SREBP‐1 induction driven by autophagy and fatty acid synthase induction, which is mediated by SREBP‐1, plays crucial roles in leptin‐stimulated metabolic reprogramming and are required for growth of breast cancer cell, suggesting a pivotal contribution of fatty acid metabolic reprogramming to tumor growth by leptin. Taken together, these results highlighted a crucial role of autophagy in leptin‐induced cancer cell‐specific metabolism, which is mediated, at least in part, via SREBP‐1 induction.
Abbreviations
- 2‐DG
- 2‐deoxyglucose
- 3‐MA
- 3‐methyladenine
- ACC‐1
- acetyl‐CoA carboxylase 1
- ACLY
- ATP citrate lyase
- ER
- estrogen receptor
- FADS1
- fatty acid desaturase 1
- FADS2
- fatty acid desaturase 2
- FAO
- fatty acid oxidation
- FAS
- fatty acid synthesis
- FASN
- fatty acid synthase
- FFA
- free fatty acid
- IHC
- immunohistochemistry
- SCD‐1
- stearoyl‐CoA desaturase‐1
- SREBP‐1
- sterol regulatory element‐binding protein 1