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1.
Romana Dolinschek Julia Hingerl Anke Benge Christian Zafiu Elisabeth Schüren EvaKathrin Ehmoser Daniela Lssner Ute Reuning 《Molecular oncology》2021,15(2):503
Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high‐affinity and constitutively signaling‐competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D‐hydrogels, involving p27kip upregulation. Moreover, it promoted EGF‐R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti‐apoptotic factors Bcl‐2 and survivin suppressing caspase activation, compared to a signaling‐incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3‐dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3‐triggered prosurvival signaling.
Abbreviations
- CLSM
- confocal laser scanning microscopy
- ECM
- extracellular matrix
- EGF‐R
- epidermal growth factor receptor
- EOC
- epithelial ovarian cancer
- FAK
- focal adhesion kinase
- FIGO
- Fédération Internationale de Gynécologie et d''Obstétrique
- GAPDH
- glyceraldehyde 3‐phosphate dehydrogenase)
- GpA
- glycophorin A
- IMD
- integrin‐mediated death
- MAPK
- mitogen‐activated protein kinases
- PI
- propidium iodide
- RGD
- Arg‐Gly‐Asp
- TMD
- transmembrane domain
2.
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
3.
4.
5.
《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
6.
《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
7.
8.
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
9.
Jeremy ArieyBonnet Kendall Carrasco Marion Le Grand Laurent Hoffer Stphane Betzi Mikael Feracci Philipp Tsvetkov Francois Devred Yves Collette Xavier Morelli Pedro Ballester Eddy Pasquier 《Molecular oncology》2020,14(12):3083
The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already‐approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro (IC50 values ranging from 288 nm to 2.1 µm). Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly upregulated at the gene level in glioblastoma as compared to normal brain tissue (fold change > 1.5; P < 0.0001). Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2, and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose‐dependent manner, with a high potency against MAPK14 (IC50 = 104 ± 46 nm). Its direct binding to MAPK14 was further validated in vitro, and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases.
Abbreviations
- BRET
- bioluminescence resonance energy transfer
- GBM
- glioblastoma
- GTeX
- Genotype‐Tissue Expression
- IC50
- half‐maximal inhibitory concentration
- ITC
- isothermal titration calorimetry
- MBZ
- mebendazole
- nanoDSF
- nanoscale differential scanning fluorimetry
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- RT
- room temperature
- siRNA
- small interfering RNA
- TCGA
- The Cancer Genome Atlas
- TSA
- thermal shift assay
10.
PengXiang Wang YunFan Sun WeiXiang Jin JianWen Cheng HaiXiang Peng Yang Xu KaiQian Zhou LiMeng Chen Kai Huang SuiYi Wu Bo Hu ZeFan Zhang Wei Guo Ya Cao Jian Zhou Jia Fan XinRong Yang 《Molecular oncology》2021,15(9):2345
Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single‐cell molecular analysis is required. We developed the ChimeraX®‐i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX®‐i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX®‐i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC‐positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single‐cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX®‐i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting.
Abbreviations
- ADABOOST
- AdaBoost classification trees
- AFP
- alpha‐fetoprotein
- AUC
- areas under the curve
- BC
- breast cancer
- BCLC
- barcelona clinic liver cancer
- BHL
- benign hepatic lesion
- CCD
- charge‐coupled device
- CHB
- chronic hepatitis B
- CK
- cytokeratin
- CNA
- copy number alteration
- CNLC
- Chinese staging for liver cancer
- CRC
- colorectal cancer
- CTC
- circulating tumor cell
- CTM
- circulating tumor microemboli
- CV
- coefficient of variation
- DAPI
- 4’,6‐diamidine‐2’‐phenylindole dihydrochloride
- EpCAM
- epithelial cell adhesion molecule
- FPR
- false‐positive rate
- GBM
- stochastic gradient boosting
- HCC
- hepatocellular carcinoma
- HD
- healthy donor
- ICC
- intrahepatic cholangiocarcinoma
- LC
- liver cirrhosis
- LCA
- lung cancer
- LOD
- limit of detection
- PBS
- phosphate‐buffered saline
- PCR
- polymerase chain reaction
- RF
- random forest
- ROC
- receiver operating characteristic
- SVM
- support vector machines
- TCGA
- The Cancer Genome Atlas
- TPR
- true‐positive rate
- TTR
- time to recurrence
- WBC
- white blood cell
- WGA
- whole‐genome amplification
- WGS
- whole‐genome sequencing
- XGB
- extreme gradient boosting
11.
Julius Semenas Tianyan Wang Azharuddin Sajid Syed Khaja AKM Firoj Mahmud Athanasios Simoulis Thomas Grundstrm Maria Fllman Jenny L. Persson 《Molecular oncology》2021,15(4):968
Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network, and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.
Abbreviations
- CRPC
- castration‐resistant prostate cancer
- DHT
- dihydrotestosterone
- E2
- estradiol
- ERα
- estrogen receptor alpha
- GO
- gene ontology
- NG‐CHM
- Next‐Generation Clustered Heatmaps
- PCa
- prostate cancer
- TMAs
- tissue microarrays
12.
Kaja C. G. Berg Tuva H. Brunsell Anita Sveen Sharmini Alagaratnam Merete Bjrnslett Merete Hektoen Kristoffer W. Brudvik Brd I. Rsok Bjrn Atle Bjrnbeth Arild Nesbakken Ragnhild A. Lothe 《Molecular oncology》2021,15(4):830
Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAF V600, and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high‐level amplifications of cancer‐critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAF V600E and TP53 co‐mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome‐wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAF V600E/TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co‐mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, P = 0.013; co‐mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co‐mutated RAS/BRAF V600E/TP53.
Abbreviations
- 5y‐CSS
- five‐year cancer‐specific survival
- CNA
- copy number aberrations
- CRC
- colorectal cancer
- CRLM
- colorectal liver metastases
- MSI
- microsatellite instable
- MSS
- microsatellite stable
13.
Lea A. Moukarzel Lorenzo Ferrando Arnaud Da Cruz Paula David N. Brown Felipe C. Geyer Fresia Pareja Salvatore Piscuoglio Anastasios D. Papanastasiou Nicola Fusco Caterina Marchi Nadeem R. AbuRustum Rajmohan Murali Edi Brogi Hannah Y. Wen Larry Norton Robert A. Soslow Anne VincentSalomon Jorge S. ReisFilho Britta Weigelt 《Molecular oncology》2021,15(4):1024
Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole‐exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial‐to‐mesenchymal transition (EMT)‐related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD‐related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
Abbreviations
- CCF
- cancer cell fraction
- CI
- clonality index
- CNA
- copy number alteration
- EMT
- epithelial‐to‐mesenchymal transition
- HRD
- homologous recombination DNA repair deficiency
- LST
- large‐scale state transition
- MBC
- metaplastic breast carcinoma
- NtAI
- numerical telomeric allelic imbalance
- SNV
- single nucleotide variant
- TCGA
- The Cancer Genome Atlas
- TNBC
- triple‐negative breast cancer
- UCS
- uterine carcinosarcoma
- WES
- whole‐exome sequencing
14.
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
15.
Lindsey M. Charo Ramez N. Eskander Ryosuke Okamura Sandip P. Patel Mina Nikanjam Richard B. Lanman David E. Piccioni Shumei Kato Michael T. McHale Razelle Kurzrock 《Molecular oncology》2021,15(1):67
Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next‐generation sequencing of plasma circulating tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real‐time representation of a tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue‐based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue‐based sequencing, enrolled in the Profile‐Related Evidence Determining Individualized Cancer Therapy () trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0–13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer. NCT02478931
Abbreviations
- BMI
- body mass index
- BRCA
- breast cancer susceptibility gene
- CAP
- College of American Pathologists
- CI
- confidence interval
- CLIA
- Clinical Laboratory Improvement Amendments
- ctDNA
- circulating tumor DNA
- Del
- deletion
- HR
- hazard ratio
- ID
- identification number
- In/del
- insertion/deletion
- MAF
- mutation allele frequency
- NR
- not reached
- OS
- overall survival
- PREDICT
- Profile‐Related Evidence Determining Individualized Cancer Therapy
- SE
- standard error
- SNV
- single nucleotide variant
- UCSD
- University of California San Diego
- VUS
- variants of unknown significance
16.
In recent years, extracellular vesicles (EVs) emerged as potential diagnostic and prognostic markers for cancer therapy. While the field of EV research is rapidly developing and their application as vehicles for therapeutic cargo is being tested, little is still known about the exact mechanisms of signaling specificity and cargo transfer by EVs, especially in vivo. Several signaling cascades have been found to use EVs for signaling in the tumor–stroma interaction. These include potentially oncogenic, verbatim transforming, signaling cascades such as Wnt and TGF‐β signaling, and other signaling cascades that have been tightly associated with tumor progression and metastasis, such as PD‐L1 and VEGF signaling. Multiple mechanisms of how these signaling cascades and EVs interplay to mediate these complex processes have been described, such as direct signal activation through pathway components on or in EVs or indirectly by influencing vesicle biogenesis, cargo sorting, or uptake dynamics. In this review, we summarize the current knowledge of EVs, their biogenesis, and our understanding of EV interactions with recipient cells with a focus on selected oncogenic and cancer‐associated signaling pathways. After an in‐depth look at how EVs mediate and influence signaling, we discuss potentially translatable EV functions and existing knowledge gaps.
Abbreviations
- EGF(R)
- epidermal growth factor (receptor)
- EMT
- epithelial–mesenchymal transition
- EP(s)
- extracellular particle(s)
- EV(s)
- extracellular vesicle(s)
- Exo(s)
- exosome(s)
- Her
- human epidermal growth factor receptor
- ISEV
- International Society for Extracellular Vesicles
- MSC
- mesenchymal stem cells
- MV(s)
- microvesicle(s)
- MVB
- multivesicular body
- PD‐L
- programmed death‐ligand
- TGF‐β
- transforming growth factor‐β
- VEGF
- vascular endothelial growth factor
- Wnt
- wingless and Int/wingless‐related integration site
17.
Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage‐associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor‐specific immune responses, thus eliciting long‐term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. Remarkably, subcutaneous injection of dying tumor cells undergoing ICD has been shown to provoke anticancer vaccine effects in vivo. DAMPs include the cell surface exposure of calreticulin (CRT) and heat‐shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high‐mobility group box‐1 (HMGB1), type I IFNs and members of the IL‐1 cytokine family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy.
Abbreviations
- ATP
- adenosine triphosphate
- BAK
- BCL‐2 homologous antagonist killer
- BAX
- BCL‐2‐associated X protein
- BCL‐2
- B‐cell lymphoma 2
- BID
- BH3‐interacting domain death agonist
- c‐FLIP
- cellular FLICE‐like inhibitory protein
- cGAMP
- cyclic guanosine monophosphate–adenosine monophosphate
- cGAS
- cyclic GMP‐AMP synthase
- CRT
- calreticulin
- CXCL10
- chemokine C‐X‐C motif ligand 10
- DAMPs
- damage‐associated molecular patterns
- DCs
- dendritic cells
- DISC
- death‐inducing signaling complex
- ER
- endoplasmic reticulum
- FADD
- FAS‐associated protein with death domain
- FASL
- FAS ligand
- GSDMD
- gasdermin D
- GSDMDNT
- N‐terminal fragment of gasdermin D
- GSDME
- gasdermin E
- HMGB1
- high‐mobility group box‐1
- HSP
- heat‐shock proteins
- Hyp‐PDT
- hypericin‐based photodynamic therapy
- ICD
- immunogenic cell death
- IFN
- interferon
- IFNAR
- IFN‐α and IFN‐β receptors
- IL
- interleukin
- IRF3
- interferon regulatory factor 3
- ISGs
- IFN‐stimulated genes
- LPS
- lipopolysaccharide
- MAPK
- mitogen‐activated protein kinase
- MHC
- major histocompatibility complex
- MLKL
- mixed‐lineage kinase‐like
- MOMP
- mitochondrial outer membrane permeabilization
- mtDNA
- mitochondrial DNA
- NF‐κB
- nuclear factor kappa‐light‐chain‐enhancer of activated B cells
- NK cells
- natural killer cells
- NLR
- NOD‐like receptor
- NLRP3
- NOD‐like receptor family, pyrin domain‐containing 3 protein
- P2RX7
- purinergic receptor P2X 7
- PD‐L1
- programmed death ligand
- PRRs
- pattern recognition receptors
- PS
- phosphatidyl serine
- RCD
- regulated cell death
- RIPK1
- receptor‐interacting serine/threonine protein kinase 1
- RIPK3
- receptor‐interacting serine/threonine protein kinase 3
- ROS
- reactive oxygen species
- STING
- stimulator of interferon genes
- tBID
- truncated form of BID
- TBK1
- TANK‐binding kinase 1
- TLR
- Toll‐like receptor
- TNF
- tumor necrosis factor
- TRAIL
- TNF‐related apoptosis‐inducing ligand
- ZBP
- Z‐DNA‐binding protein
18.
Pauline A. J. Mendelaar Jaco Kraan Mai Van Leonie L. Zeune Leon W. M. M. Terstappen Esther Oomende Hoop John W. M. Martens Stefan Sleijfer 《Molecular oncology》2021,15(1):116
Circulating tumor cells (CTCs) in the blood of cancer patients are of high clinical relevance. Since detection and isolation of CTCs often rely on cell dimensions, knowledge of their size is key. We analyzed the median CTC size in a large cohort of breast (BC), prostate (PC), colorectal (CRC), and bladder (BLC) cancer patients. Images of patient‐derived CTCs acquired on cartridges of the FDA‐cleared CellSearch® method were retrospectively collected and automatically re‐analyzed using the accept software package. The median CTC diameter (μm) was computed per tumor type. The size differences between the different tumor types and references (tumor cell lines and leukocytes) were nonparametrically tested. A total of 1962 CellSearch® cartridges containing 71 612 CTCs were included. In BC, the median computed diameter (CD) of patient‐derived CTCs was 12.4 μm vs 18.4 μm for cultured cell line cells. For PC, CDs were 10.3 μm for CTCs vs 20.7 μm for cultured cell line cells. CDs for CTCs of CRC and BLC were 7.5 μm and 8.6 μm, respectively. Finally, leukocytes were 9.4 μm. CTC size differed statistically significantly between the four tumor types and between CTCs and the reference data. CTC size differences between tumor types are striking and CTCs are smaller than cell line tumor cells, whose size is often used as reference when developing CTC analysis methods. Based on our data, we suggest that the size of CTCs matters and should be kept in mind when designing and optimizing size‐based isolation methods.
Abbreviations
- ACCEPT
- Automated CTC Classification, Enumeration, and PhenoTyping software
- BC
- breast cancer
- BLC
- bladder cancer
- CD
- computed diameter
- CEL
- cultured tumor cell (cell line)
- CK
- cytokeratin
- CRC
- colorectal cancer
- CTC‐L
- circulating tumor cells derived from cerebrospinal fluid (liquor)
- CTCs
- circulating tumor cells
- DAPI
- 4′6‐diamidino‐2‐phenylindole
- EMT
- epithelial–mesenchymal transition
- EpCAM
- epithelial cell adhesion molecule
- IQR
- interquartile range
- KW test
- Kruskal–Wallis test
- MWU test
- Mann–Whitney U test
- NCR
- nucleus/cytoplasm ratio
- P2A
- perimeter to area
- PC
- prostate cancer
- TIF
- tagged Image Format files
- TXT
- text file
- μm
- micrometer
- µm2
- square micrometers
19.
Naomichi Koga Qingjiang Hu Akihiro Sakai Kazuki Takada Ryota Nakanishi Yuichi Hisamatsu Koji Ando Yasue Kimura Eiji Oki Yoshinao Oda Masaki Mori 《Cancer science》2021,112(8):3018
Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47‐SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death‐ligand 1 (PD‐L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8+ T cells, and PD‐L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD‐L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD‐1‐PD‐L1 blockade. 相似文献