Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 11, 2021

Abstract Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally adenocarcinoma. The cellular heterogeneity molecular events underlying this stepwise progression remain unclear. In study, we perform single-cell RNA sequencing of 268,471 cells collected 25 patients four histologic stages LUAD compare them to normal cell types. We detect a group closely resembling alveolar type 2 (AT2) that emerged during hyperplasia whose transcriptional profile began diverge AT2 progressed, taking on feature characteristic stem-like cells. identify genes related energy metabolism ribosome synthesis are upregulated early may promote progression. MDK TIMP1 could be potential biomarkers for understanding pathogenesis. Our work shed light the signatures distinct our findings facilitate diagnosis.

Language: Английский

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SPP1 promotes ovarian cancer progression via Integrin β1/FAK/Akt signaling pathway

OncoTargets and Therapy, Journal Year: 2018, Volume and Issue: Volume 11, P. 1333 - 1343

Published: March 1, 2018

Ovarian cancer is one of the most lethal malignant tumors in women. Secreted phosphoprotein 1 (SPP1) plays an important role some types. Therefore, SPP1 ovarian was determined and potential mechanism elucidated.

Language: Английский

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LncRNA SLCO4A1-AS1 facilitates growth and metastasis of colorectal cancer through β-catenin-dependent Wnt pathway

Journal of Experimental & Clinical Cancer Research, Journal Year: 2018, Volume and Issue: 37(1)

Published: Sept. 10, 2018

Emerging evidence has shown long noncoding RNAs (lncRNAs) exert important roles in colorectal cancer (CRC) tumorigenesis. However, most lncRNAs involved this process remain undefined and the underlying molecular mechanisms mediated by are largely unknown. An unbiased screening was used to identify novel CRC according an online-available data dataset. In situ hybridization (ISH) qRT-PCR detect lncRNA expression patterns. CCK8, colony formation, fluorescence activated cell sorter (FACS), transwell, xenograft nude mouse model western blot assays were analyze functions of SLCO4A1-AS1. RNA-pulldown, blot, RNA (RNA-FISH) electrophoretic mobility shift assay (EMSA) utilized explore mechanism LncRNA SLCO4A1-AS1 significantly upregulated tissues its overexpression closely related with poor prognosis tumor metastasis. By knocking down SLCO4A1-AS1, we found that promoted proliferation, migration, invasion epithelial–mesenchymal transition (EMT) cells vitro, as well inhibited apoptosis. Moreover, dramatically delayed propagation vivo. Mechanistically, activates Wnt/β-catenin signaling. enhanced stability β-catenin impairing interaction GSKβ inhibiting phosphorylation. Finally, restoration protein level rescued migration SLCO4A1-AS1-depleted cells. serves oncogenic role through activating signaling pathway. And might be a useful biomarker for diagnosis prognosis.

Language: Английский

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Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer

Cancer Cell International, Journal Year: 2021, Volume and Issue: 21(1)

Published: Oct. 20, 2021

Cancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, could serve as a promising therapeutic target. Our purpose was construct CAF-related prognostic signature for CRC.We performed bioinformatics analysis on single-cell transcriptome data derived from Gene Expression Omnibus (GEO) identified 208 differentially expressed cell markers cluster. Bulk gene expression of CRC obtained The Cancer Genome Atlas (TCGA) GEO databases. Univariate Cox regression least absolute shrinkage operator (LASSO) analyses were TCGA training cohort (n = 308) model construction, validated in validation 133), total 441), GSE39582 470) GSE17536 177) datasets. Microenvironment Cell Populations-counter (MCP-counter) Estimate the Proportion Immune cells (EPIC) methods applied evaluated CAFs infiltrations bulk data. Real-time polymerase chain reaction (qPCR) tissue microarrays containing 80 colon samples further validate value CAF model. pRRophetic Tumor Dysfunction Exclusion (TIDE) algorithms utilized predict chemosensitivity immunotherapy response. Human Protein (HPA) databases immunohistochemistry used evaluate protein expressions.A nine-gene established cohort. Kaplan-Meier survival revealed patients with higher risk scores correlated adverse prognosis each MCP-counter EPIC results consistently significantly high group. Patients more prone not respond immunotherapy, but sensitive several conventional chemotherapeutics, suggesting potential strategy combining chemotherapy anti-CAF therapy improve efficacy current T-cell based immunotherapies. multivariate verified an independent indicator predicting overall survival, CAF-based nomogram then built clinical utility CRC.To conclude, robust CRC, which provides novel genomics evidence immunotherapeutic strategies.

Language: Английский

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A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(9), P. 4999 - 5009

Published: May 7, 2020

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, time-to-cancer. PTSD associated premature mortality frequently has comorbid physical illnesses suggestive accelerated aging. This the first study assess DNAm GrimAge patients. We investigated acceleration relative denoted "AgeAccelGrim" combat trauma-exposed male veterans without using cross-sectional longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher group compared control (N = 162, 1.26 vs −0.57, p 0.001 N 53, 0.93 −1.60 Years, 0.008), suggesting aging cohorts PTSD. 3-year follow-up individuals initially diagnosed 26), changes symptom severity were correlated (r 0.39, 0.049). addition, loss CD28 cell surface markers on CD8 + T cells, T-cell senescence/exhaustion that aging, positively AgeAccelGrim, immunological contribution Overall, our findings delineate cellular correlates combat-related PTSD, which may help explain increased medical morbidity seen this disease.

Language: Английский

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m⁶A RNA modification modulates PI3K/Akt/mTOR signal pathway in Gastrointestinal Cancer

Theranostics, Journal Year: 2020, Volume and Issue: 10(21), P. 9528 - 9543

Published: Jan. 1, 2020

Rationale: Methylation at the N6 position of adenosine (m6A) is most prevalent RNA modification within protein-coding mRNAs in mammals, and it a reversible with various important biological functions. The formation function m6A are regulated by methyltransferases (writers), demethylases (erasers), special binding proteins (readers) as key factors. However, underlying mechanisms gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling nine known writer, eraser, reader GI cancer. Methods: Data from Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) were used. alteration pathway analysis done cBioportal. protein network regulators its related members was analyzed STRING online platform. Phylogenetic tree constructed MEGA7. sites predicted SRAMP. SNPs m6ASNP. modulation on validated m6A-seq, real-time PCR phosphor-MAPK array. Results: We found that mostly upregulated their differential expression significantly influenced overall survival patients phosphatidylinositol-3-kinase (PI3K)/Akt mammalian target rapamycin (mTOR) signaling pathways to be potentially affected human cancers, including cancer, which further verified m6A-Seq phospho-MAPK Conclusions: Our findings suggest has fundamental role regulation PI3K/Akt mTOR

Language: Английский

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TIMP1 derived from pancreatic cancer cells stimulates Schwann cells and promotes the occurrence of perineural invasion

Cancer Letters, Journal Year: 2022, Volume and Issue: 546, P. 215863 - 215863

Published: Aug. 9, 2022

Language: Английский

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Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection

Cancers, Journal Year: 2022, Volume and Issue: 14(8), P. 1889 - 1889

Published: April 8, 2022

Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of cancers, few molecular approaches to detect CRC exist. Carcinoembryonic antigen (CEA) a known serum biomarker that used in for monitoring disease recurrence or response treatment. However, it can also be raised multiple benign conditions, thus having no value early detection screening CRC. Molecular biomarkers play an ever-increasing role diagnosis, prognosis, outcome prediction disease, however, only limited number are available none suitable A PCR-based Epi proColon® blood plasma test methylated SEPT9 has been approved by USFDA USA, alongside stool DNA from cells. these reserved patients who decline traditional methods. There remains urgent need development non-invasive highly specific sensitive routinely screening. approach discovery focuses on analysis transcriptome cells identify differentially expressed genes proteins. systematic search literature yielded 100 markers, which vast majority overexpressed In terms function, they largely belong biological pathways involved cell division, regulation gene expression, proliferation, name few. This review evaluates current methods screening, availability biomarkers, advances within field diagnosis

Language: Английский

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Extracellular Vesicles as Regulators of the Extracellular Matrix

Bioengineering, Journal Year: 2023, Volume and Issue: 10(2), P. 136 - 136

Published: Jan. 19, 2023

Extracellular vesicles (EVs) are small membrane-bound secreted into the extracellular space by all cell types. EVs transfer their cargo which includes nucleic acids, proteins, and lipids to facilitate cell-to-cell communication. As released move from parent recipient cell, interact with matrix (ECM) acts as a physical scaffold for organization function of cells. Recent work has shown that can modulate act regulators ECM. This review will first discuss EV biogenesis mechanism transported through Additionally, we how contribute structural components aid in degradation Lastly, role influencing cells remodel ECM both pathological therapeutic contexts is examined.

Language: Английский

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Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Jan. 24, 2023

Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one the limited therapies available. However, only subgroup uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode vascularization specific histopathological growth patterns (HGPs), which have proven prognostic predictive significance. Nevertheless, molecular mechanisms poorly understood.We evaluated CRCLM from 225 patients regarding HGP clinical data. Moreover, we performed spatial (21,804 spots) single-cell (22,419 cells) RNA sequencing analyses explore differences in detail, further validated vitro immunohistochemical analysis patient-derived organoid cultures.We detected metabolic alterations signature WNT signalling activation metastatic cells related VCO phenotype. Importantly, corresponding healthy displaying angiogenesis, identified predominantly expressed capillary subtype endothelial cells, could be explored as possible predictor for relying angiogenesis.These findings may prove novel therapeutic targets treatment CRCLM, special ones VCO.

Language: Английский

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