scholarly journals Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinfen Wei ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Ziqing He ◽  
Dawei Jiang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Matrix Remodeling ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Associated Macrophage ◽  
Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

scholarly journals A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

2019 ◽  
Author(s):  
Federico Bocci ◽  
Mohit Kumar Jolly ◽  
José Nelson Onuchic
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Single Cell ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Biophysical Model ◽  
Size Distributions ◽  
Cancer Cell Migration ◽  
Mesenchymal Transition ◽  
Cancer Types

AbstractThe gain of cellular motility via the epithelial-mesenchymal transition (EMT) is considered crucial in the metastatic cascade. Cells undergoing EMT to varying extents are launched into the bloodstream as single circulating tumor cells (CTCs) or multi-cellular clusters. The frequency and size distributions of these multi-cellular clusters has been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the epithelial-mesenchymal phenotypic transition and cell migration to explain these different modes of cancer cell migration. With this reduced physical model, we identify a transition from individual migration to clustered cell migration that is regulated by the rate of EMT and the degree of cooperativity between cells during migration. This single cell to clustered migration transition can robustly recapitulate cluster size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms of cell migration during metastasis. Furthermore, we identify three main mechanisms that can facilitate the formation and dissemination of large clusters: first, mechanisms that prevent a complete EMT and instead increase the population of hybrid Epithelial/Mesenchymal (E/M) cells; second, multiple intermediate E/M states that give rise to heterogeneous clusters formed by cells with different epithelial-mesenchymal traits; and third, non-cell-autonomous induction of EMT via cell-to-cell signaling that gives rise to spatial correlations among cells in a tissue. Overall, this biophysical model represents a first step toward bridging the gap between the molecular and biophysical understanding of EMT and various modes of cancer cell migration, and highlights that a complete EMT might not be required for metastasis.Popular summaryThe Epithelial-Mesenchymal Transition (EMT) has been identified as the first step that enables cancer metastases; through this process, cancer cells gain the motility necessary to migrate and invade. Cancer cells that undergo EMT can enter the circulatory system both as single cells or as multi-cellular clusters. While single cells are generally more frequent in human cancers, clusters are more prevalent in aggressive cancers that metastasize more. Although the molecular mechanisms of EMT are relatively conserved across cancers, how different cancers exhibit such tremendous variability in terms of cell migration remains unclear. We develop a biophysical model to investigate how EMT regulation at a single cell level can give rise to single cell and clustered cell migration. This model quantitatively reproduces size distributions of circulating tumor cell clusters reported in human circulation and mouse models, therefore identifying a unifying set of principles governing cell migration across different cancer types. Moreover, a model where cells only undergo a partial EMT to a hybrid epithelial/mesenchymal state can recapitulate different features observed in collective cancer cell migration, including the frequency of large clusters and flat distributions that cannot be captured by a model of complete EMT. Besides partial EMT, we propose additional mechanisms that can facilitate the formation of large tumor cell clusters, including multiple hybrid epithelial/mesenchymal cell states and signaling between cells that enables noncell autonomous EMT induction. Therefore, our general picture suggests universal traits in the migration of cancer cells and challenges the necessity of a complete EMT for cancer metastasis.

scholarly journals Recurrence of cancer cell states across diverse tumors and their interactions with the microenvironment

2021 ◽  
Author(s):  
Dalia Barkley ◽  
Reuben Moncada ◽  
Maayan Pour ◽  
Deborah Liberman ◽  
Ian Dryg ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Location ◽  
Interferon Response ◽  
Mesenchymal Transition ◽  
Cancer Types ◽  
Tumor Types

While genetic tumor heterogeneity has long been recognized, recent work has revealed significant variation among cancer cells at the epigenetic and transcriptional levels. Profiling tumors at the single-cell level in individual cancer types has shown that transcriptional heterogeneity is organized into cancer cell states, implying that diverse cell states may represent stable and functional units with complementary roles in tumor maintenance and progression. However, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Furthermore, the role of cancer cell states in tumor progression and their specific interactions with cells of the tumor microenvironment remain to be elucidated. Here, we perform a pan-cancer single-cell RNA-Seq analysis across 15 cancer types and identify a catalog of 16 gene modules whose expression defines recurrent cancer cell states, including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Using mouse models, we find that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Moreover, spatial transcriptomic analysis further links the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance, and metastasis.

scholarly journals Single-Cell RNA-Seq Analysis Reveals the Acquisition of Cancer Stem Cell Traits and Increase of Cell–Cell Signaling during EMT Progression

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5726
Author(s):  
Federico Bocci ◽  
Peijie Zhou ◽  
Qing Nie
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Signaling ◽  
Single Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Intermediate Cell ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Cell Cell

Intermediate cell states (ICSs) during the epithelial–mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell–cell signaling. To accomplish this task, we integrate computational methods for clustering and trajectory inference with analysis of EMT gene signatures, CSC markers, and cell–cell signaling pathways, and highlight conserved and specific processes across the datasets. Our analysis reveals that “standard” measures of pluripotency often used in developmental contexts do not necessarily correlate with EMT progression and expression of CSC-related markers. Conversely, an EMT circuit energy that quantifies the co-expression of epithelial and mesenchymal genes consistently increases along EMT trajectories across different cancer types and anatomical locations. Moreover, despite the high context specificity of signal transduction across different cell types, cells undergoing EMT always increased their potential to send and receive signals from other cells.

scholarly journals Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 89
Author(s):  
Ha Thi Thu Do ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

scholarly journals Snail Overexpression Alters the microRNA Content of Extracellular Vesicles Released from HT29 Colorectal Cancer Cells and Activates Pro-Inflammatory State In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 172
Author(s):  
Izabela Papiewska-Pająk ◽  
Patrycja Przygodzka ◽  
Damian Krzyżanowski ◽  
Kamila Soboska ◽  
Izabela Szulc-Kiełbik ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells ◽  
Microrna Profile ◽  
Inflammatory State ◽  
Metastatic Process

During metastasis, cancer cells undergo phenotype changes in the epithelial-mesenchymal transition (EMT) process. Extracellular vesicles (EVs) released by cancer cells are the mediators of intercellular communication and play a role in metastatic process. Knowledge of factors that influence the modifications of the pre-metastatic niche for the migrating carcinoma cells is important for prevention of metastasis. We focus here on how cancer progression is affected by EVs released from either epithelial-like HT29-cells or from cells that are in early EMT stage triggered by Snail transcription factor (HT29-Snail). We found that EVs released from HT29-Snail, as compared to HT29-pcDNA cells, have a different microRNA profile. We observed the presence of interstitial pneumonias in the lungs of mice injected with HT29-Snail cells and the percent of mice with lung inflammation was higher after injection of HT29-Snail-EVs. Incorporation of EVs released from HT29-pcDNA, but not released from HT29-Snail, leads to the increased secretion of IL-8 from macrophages. We conclude that Snail modifications of CRC cells towards more invasive phenotype also alter the microRNA cargo of released EVs. The content of cell-released EVs may serve as a biomarker that denotes the stage of CRC and EVs-specific microRNAs may be a target to prevent cancer progression.

scholarly journals MBP-1 Suppresses Growth and Metastasis of Gastric Cancer Cells through COX-2

2009 ◽  
Vol 20 (24) ◽  
pp. 5127-5137 ◽  
Author(s):  
Kai-Wen Hsu ◽  
Rong-Hong Hsieh ◽  
Chew-Wun Wu ◽  
Chin-Wen Chi ◽  
Yan-Hwa Wu Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Suppressive Effect ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition ◽  
Cox 2

The c-Myc promoter binding protein 1 (MBP-1) is a transcriptional suppressor of c-myc expression and involved in control of tumorigenesis. Gastric cancer is one of the most frequent neoplasms and lethal malignancies worldwide. So far, the regulatory mechanism of its aggressiveness has not been clearly characterized. Here we studied roles of MBP-1 in gastric cancer progression. We found that cell proliferation was inhibited by MBP-1 overexpression in human stomach adenocarcinoma SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by MBP-1 overexpression but promoted by MBP-1 knockdown. Furthermore, the xenografted tumor growth of SC-M1 cells was suppressed by MBP-1 overexpression. Metastasis in lungs of mice was inhibited by MBP-1 after tail vein injection with SC-M1 cells. MBP-1 also suppressed epithelial-mesenchymal transition in SC-M1 cells. Additionally, MBP-1 bound on cyclooxygenase 2 (COX-2) promoter and downregulated COX-2 expression. The MBP-1-suppressed tumor progression in SC-M1 cells were through inhibition of COX-2 expression. MBP-1 also exerted a suppressive effect on tumor progression of other gastric cancer cells such as AGS and NUGC-3 cells. Taken together, these results suggest that MBP-1–suppressed COX-2 expression plays an important role in the inhibition of growth and progression of gastric cancer.

scholarly journals Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yifan Wang ◽  
Ruocen Liao ◽  
Xingyu Chen ◽  
Xuhua Ying ◽  
Guanping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Invasive Breast Cancer ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

scholarly journals FSCN1 Promotes Epithelial-Mesenchymal Transition Through Increasing Snail1 in Ovarian Cancer Cells

2018 ◽  
Vol 49 (5) ◽  
pp. 1766-1777 ◽  
Author(s):  
Jie Li ◽  
Songlin Zhang ◽  
Meili Pei ◽  
Lei Wu ◽  
Yanli Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Transwell Assay ◽  
Mesenchymal Transition ◽  
Novel Target ◽  
Snail1 Expression

Background/Aims: Epithelial-mesenchymal transition (EMT) is one of the key mechanisms mediating cancer progression. Snail1 has a pivotal role in the regulation of EMT, involving the loss of E-cadherin and concomitant upregulation of vimentin, among other biomarkers. We have found FSCN1 promoted EMT in ovarian cancer cells, but the precise mechanism of FSCN1 in EMT process has not been clearly elucidated. Methods: The levels of FSCN1 and snail1 were determined in epithelial ovarian cancer(EOC) specimen and in ovarian cancer cells by RT-qPCR. The changes of EMT makers and effects on snail1 by FSCN1 were examined by overexpression or depletion of FSCN1 in EOC cells by RT-qPCR and western blotting. The invasiveness of the FSCN1-modified EOC cells was examined in transwell assay. Co-immunoprecipitation (IP) was performed to detect the interaction between snail1 and FSCN1 in EOC cells. Results: We found FSCN1 and snail1 significantly increased in EOC, and especially in EOC with metastasis. FSCN1 was positively correlated with snail1 expression at the cellular/histological levels. Moreover, we further showed that FSCN1 physiologically interacted with and increased the levels of snail1 to promote ovarian cancer cell EMT. Conclusion: FSCN1 promote EMT through snail1 in ovarian cancer cells. FSCN1 is an attractive novel target for inhibiting invasion and metastasis of EOC cells.

scholarly journals Single Cell Hydrodynamic Stretching and Microsieve Filtration Reveal Genetic, Phenotypic and Treatment-Related Links to Cellular Deformability

Micromachines ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 486
Author(s):  
Fenfang Li ◽  
Igor Cima ◽  
Jess Honganh Vo ◽  
Min-Han Tan ◽  
Claus Dieter Ohl
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Extensional Flow ◽  
Colorectal Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Cellular Models ◽  
Cellular Deformability

Deformability is shown to correlate with the invasiveness and metastasis of cancer cells. Recent studies suggest epithelial-to-mesenchymal transition (EMT) might enable cancer metastasis. However, the correlation of EMT with cancer cell deformability has not been well elucidated. Cellular deformability could also help evaluate the drug response of cancer cells. Here, we combine hydrodynamic stretching and microsieve filtration to study cellular deformability in several cellular models. Hydrodynamic stretching uses extensional flow to rapidly quantify cellular deformability and size with high throughput at the single cell level. Microsieve filtration can rapidly estimate relative deformability in cellular populations. We show that colorectal cancer cell line RKO with the mesenchymal-like feature is more flexible than the epithelial-like HCT116. In another model, the breast epithelial cells MCF10A with deletion of the TP53 gene are also significantly more deformable compared to their isogenic wildtype counterpart, indicating a potential genetic link to cellular deformability. We also find that the drug docetaxel leads to an increase in the size of A549 lung cancer cells. The ability to associate mechanical properties of cancer cells with their phenotypes and genetics using single cell hydrodynamic stretching or the microsieve may help to deepen our understanding of the basic properties of cancer progression.

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