Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer

Fu, Fangmei; Yang, Xudong; Zheng, Minying; Zhao, Qi; Zhang, Kexin; Li, Zugui; Zhang, Hao

doi:10.3389/fmolb.2020.00202

Cited by 31 publications

(52 citation statements)

References 127 publications

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“…With the accumulating evidence for TM4SF1's role in cancer, potential oncologic therapies have been investigated such as in a phase 1/2 clinical trial evaluating chimeric antigen receptor T-cells (CAR-T) to treat patients with TM4SF1-positive pancreatic, colorectal, gastric, and lung cancer (ClinicalTrials NCT04151186). TM4SF1 promotes the migration and invasion of cancer cells by inducing EMT, self-renewal ability, and tumor angiogenesis (26), all of which are mechanisms relevant to the pathological pulmonary vascular remodeling in PAH.…”

Section: Discussionmentioning

confidence: 99%

“…Tm4sf1 was the top upregulated DEG in EA2 vs. EA1 and its expression was specific to EA2 when comparing all lung cell types (Figure E2). Tm4sf1 encodes the cell-surface protein transmembrane 4 L six family member 1 which plays a role in the regulation of cell development, growth and motility and has been strongly implicated in various cancers (26) but has never before been studied in PAH. Given the importance of cancer-related processes and their overlap with PAH (27), we paid closer attention to the Tm4sf1-marked subpopulation of endothelial cells, EA2.…”

Section: Tm4sf1-marked Subpopulation Of Endothelial Cells Expresses a Distinct Transcriptomic Signature Relevant To Pahmentioning

confidence: 99%

“…Given the strong connection between Tm4sf1 and various cancers (26), we then evaluated the response of Tm4sf1 and other signature genes of EA2 to phorbol 12-myristate 13-acetate (PMA), a potent tumor promoter which activates protein kinase C and downstream mitogen-activated protein kinase (MAPK) pathways which have been implicated in PAH pathogenesis (52)(53)(54). We found that TM4SF1 was upregulated in BMPR2-silenced human PAECs exposed to PMA (Figure 5L), while PROCR, SULF1, and NOSTRIN were either downregulated or unchanged (Figures 5M-5O).…”

Section: Ea2 Signature Genes Are Differentially Regulated In the Lungs Of Pah Patients And In Pah Models Of Human Endothelial Cellsmentioning

confidence: 99%

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A Tm4sf1-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension

Hong

Wong

Huynh

et al. 2022

Preprint

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Rationale: The identification and role of endothelial progenitor cells (EPCs) in pulmonary arterial hypertension (PAH) remains controversial. Single-cell omics analysis can shed light on EPCs and their potential contribution to PAH pathobiology. Objectives: We aim to identify EPCs in rat lungs and assess their relevance to preclinical and human PAH. Methods: Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA-seq of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic datasets. Measurements and Main Results: A subpopulation of endothelial cells (EA2) marked by Tm4sf1, a gene strongly implicated in cancer, harbored a distinct transcriptomic signature including Bmpr2 downregulation that was enriched for pathways such as inflammation and angiogenesis. Cell-to-cell communication networks specific to EA2 were activated in PAH such as CXCL12 signaling. Trajectory analysis demonstrated EA2 has a stem/progenitor cell phenotype. Analysis of independent datasets revealed Tm4sf1 is a marker for hematopoietic stem cells and is upregulated in PAH peripheral blood, particularly in patients with worse WHO functional class. EA2 signature genes including Procr and Sulf1 were found to be differentially regulated in the lungs of PAH patients and in PAH models in vitro, such as BMPR2 knockdown. Conclusions: Our study uncovered a novel Tm4sf1-marked stem/progenitor subpopulation of rat lung endothelial cells and demonstrated its relevance to preclinical and human PAH. Future experimental studies are warranted to further elucidate the pathogenic role and therapeutic potential of targeting EA2 and Tm4sf1 in PAH.

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Section: Discussionmentioning

confidence: 99%

Section: Tm4sf1-marked Subpopulation Of Endothelial Cells Expresses a Distinct Transcriptomic Signature Relevant To Pahmentioning

confidence: 99%

Section: Ea2 Signature Genes Are Differentially Regulated In the Lungs Of Pah Patients And In Pah Models Of Human Endothelial Cellsmentioning

confidence: 99%

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A Tm4sf1-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension

Hong

Wong

Huynh

et al. 2022

Preprint

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“…TM4SF1 is upregulated in several epithelial cancers [ 46 ], including bladder cancer [ 47 ], and promotes the proliferation, migration and invasion of cancer cells by inducing EMT and cancer stemness [ 46 , 48 , 49 ]. Importantly, several studies have shown that TM4SF1 expression is positively correlated with chemotherapy resistance in multiple cancers [ 46 , 50 , 51 ]. IGFBP3 plays a key role in esophageal tumor progression and metastasis by facilitating EMT [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

Font

Porras

Valderrama

et al. 2021

Cancers

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In the phase II MAJA trial, maintenance therapy with vinflunine resulted in longer progression-free survival compared to best supportive care in advanced urothelial cell carcinoma (aUCC) patients who did not progress after first-line platinum-based chemotherapy. However, despite an initial benefit observed in some patients, unequivocal resistance appears which underlying mechanisms are presently unknown. We have performed gene expression and functional enrichment analyses to shed light on the discovery of these underlying resistance mechanisms. Differential gene expression profile of eight patients with poor outcome and nine with good outcome to vinflunine administered in the MAJA trial were analyzed. RNA was isolated from tumor tissue and gene expression was assessed by microarray. Differential expression was determined with linear models for microarray data. Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the genes. In vitro functional studies were performed using UCC cell lines. Hierarchical clustering showed a differential gene expression pattern between patients with good and poor outcome to vinflunine treatment. GSEA identified epithelial-to-mesenchymal transition (EMT) as the top negatively enriched hallmark in patients with good outcome. In vitro analyses showed that the polyphenol curcumin downregulated EMT markers and sensitized UCC cells to vinflunine. We conclude that EMT mediates resistance to vinflunine and suggest that the reversion of this process could enhance the effect of vinflunine in aUCC patients.

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“…TM4SF1 has been found to be overexpressed in pancreatic cancer and has roles in apoptosis, proliferation, and cell migration [34]. Previous work found that collagen 1 (GO:0030199) binds with DDR1 which then interacts with TM4SF1 to activate the focal adhesion kinase (FAK) [34,51,52].…”

Section: Spcs Enhances Biological Interpretabilitymentioning

confidence: 99%

SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression

Liu

Duggan

Huang

et al. 2021

Preprint

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The recently developed spatial transcriptomics (ST) technique has made it possible to view spatial transcriptional heterogeneity in a high throughput manner. It is based on highly multiplexed sequence analysis and uses barcodes to split the sequenced reads into respective tissue locations. However, this type of sequencing technique suffers from high noise and drop-out events in the data, which makes smoothing a necessary step before performing downstream analysis. Traditional smoothing methods used in the similar single cell RNA sequencing (scRNA-seq) data are one-factor methods that can only utilize associations in transcriptome space. Since they do not account for associations in the Euclidean space, i.e. tissue location distances on the ST slide, these one-factor methods cannot take full advantage of all the knowledge in ST data. In this study, we present a novel two-factor smoothing technique, Spatial and Pattern Combined Smoothing (SPCS), that employs k-nearest neighbor technique to utilize associations from transcriptome and Euclidean space from the ST data. By performing SPCS on 10 ST slides from pancreatic ductal adenocarcinoma (PDAC), smoothed ST slides have better separability, partition accuracy, and biological interpretability than the ones smoothed by pre-existing one-factor smoothing methods. Source code of SPCS is provided in Github (https://github.com/Usos/SPCS).

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Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer

Cited by 31 publications

References 127 publications

A Tm4sf1-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension

A Tm4sf1-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression

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