Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

Wang, Yuqi; Niu, Zubiao; Zhou, Lülin; Zhou, Yunyun; Ma, Qi; Zhu, Yichao; Liu, Mengzhe; Shi, Yingjie; Tai, Yoshiaki; Shao, Qing; Ge, Jianlin; Hua, Jilei; Gao, Lihua; Huang, Hongyan; Jiang, Hong; Sun, Qiang

doi:10.3389/fonc.2021.670051

Cited by 15 publications

(10 citation statements)

References 47 publications

(51 reference statements)

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“…On one hand, SARS-CoV-2 infection could induce syncytia formation in a way dependent on the presence of a unique bi-arginine motif around the furin cleavage site that dictates cell-cell fusion [ 6 ]. The syncytia resulting from infection-induced cell-cell fusion may actively internalize lymphocytes to form heterotypic cell-in-cell structures [ 6 , 38 ], a pathological phenotype mostly documented in human tumors [ 39 – 44 ], and genetically controlled by a set of core elements, including adherens junctions, actomyosin and mechanical ring [ 45 – 49 ]. The formation of cell-in-cell structure frequently leads to the death of the internalized lymphocytes in an acidified lysosome [ 6 , 50 – 52 ], contributing to lymphopenia which was believed to be a causal factor linked to severe COVID-19 [ 53 – 56 ].…”

Section: Discussionmentioning

confidence: 99%

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

et al. 2022

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Background Rodents, such as mice, are vulnerable targets, and potential intermediate hosts, of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, and Omicron. N501Y in the receptor-binding domain (RBD) of Spike protein is the key mutation dictating the mouse infectivity, on which the neighboring mutations within RBD have profound impacts. However, the impacts of mutations outside RBD on N501Y-mediated mouse infectivity remain to be explored. Results Herein, we report that two non-RBD mutations derived from mouse-adapted strain, Ins215KLRS in the N-terminal domain (NTD) and H655Y in the subdomain linking S1 to S2, enhance mouse infectivity in the presence of N501Y mutation, either alone or together. This is associated with increased interaction of Spike with mouse ACE2 and mutations-induced local conformation changes in Spike protein. Mechanistically, the H655Y mutation disrupts interaction with N657, resulting in a less tight loop that wraps the furin-cleavage finger; and the insertion of 215KLRS in NTD increases its intramolecular interaction with a peptide chain that interfaced with the RBD-proximal region of the neighboring protomer, leading to a more flexible RBD that facilitates receptor binding. Moreover, the Omicron Spike that contains Ins214EPE and H655Y mutations confer mouse infectivity > 50 times over the N501Y mutant, which could be effectively suppressed by mutating them back to wild type. Conclusions Collectively, our study sheds light on the cooperation between distant Spike mutations in promoting virus infectivity, which may undermine the high infectiousness of Omicron variants towards mice.

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Section: Discussionmentioning

confidence: 99%

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

et al. 2022

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“…We recently summarized the clinical significance of entotic figures in cancers [7]. Since then, it has been reported that homotypic CIC structures preferentially impact the survival of patients with a late stage of esophageal carcinoma [92]. However, using the published approach, entotic CICs and cannibalistic CICs cannot be distinguished.…”

Section: Entosismentioning

confidence: 99%

Classification of Cell-in-Cell Structures: Different Phenomena with Similar Appearance

Borensztejn¹,

Tyrna²,

Gaweł³

et al. 2021

Cells

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A phenomenon known for over 100 years named “cell-in-cell” (CIC) is now undergoing its renaissance, mostly due to modern cell visualization techniques. It is no longer an esoteric process studied by a few cell biologists, as there is increasing evidence that CICs may have prognostic and diagnostic value for cancer patients. There are many unresolved questions stemming from the difficulties in studying CICs and the limitations of current molecular techniques. CIC formation involves a dynamic interaction between an outer or engulfing cell and an inner or engulfed cell, which can be of the same (homotypic) or different kind (heterotypic). Either one of those cells appears to be able to initiate this process, which involves signaling through cell–cell adhesion, followed by cytoskeleton activation, leading to the deformation of the cellular membrane and movements of both cells that subsequently result in CICs. This review focuses on the distinction of five known forms of CIC (cell cannibalism, phagoptosis, enclysis, entosis, and emperipolesis), their unique features, characteristics, and underlying molecular mechanisms.

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“…CICs were most frequently documented in a variety of human tumor tissues [32][33][34][35], where CICs could promote clonal selection and tumor evolution as a mechanism of cell competition [1,36,37], or compromise tumor growth via mediating the in-cell killing by immune cells [38]. Accordingly, CICs and their subtypes had been shown to be an independent prognostic factor for cancer patients [39][40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Tumor malignancy by genetic transfer between cells forming cell-in-cell structures

Wang

Zhong

Wang³

et al. 2023

Cell Death Dis

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Cell-in-cell structures (CICs) refer to a type of unique structure with one or more cells within another one, whose biological outcomes are poorly understood. The present study aims to investigate the effects of CICs formation on tumor progression. Using genetically marked hepatocellular cancer cell lines, we explored the possibility that tumor cells might acquire genetic information and malignant phenotypes from parental cells undergoing CICs formation. The present study showed that the derivatives, isolated from CICs formed between two subpopulations by flow cytometry sorting, were found to inherit aggressive features from the parental cells, manifested with increased abilities in both proliferation and invasiveness. Consistently, the CICs clones expressed a lower level of E-cadherin and a higher level of Vimentin, ZEB-1, Fibronectin, MMP9, MMP2 and Snail as compared with the parental cells, indicating epithelial-mesenchymal transition. Remarkably, the new derivatives exhibited significantly enhanced tumorigenicity in the xenograft mouse models. Moreover, whole exome sequencing analysis identified a group of potential genes which were involved in CIC-mediated genetic transfer. These results are consistent with a role of genetic transfer by CICs formation in genomic instability and malignancy of tumor cells, which suggest that the formation of CICs may promote genetic transfer and gain of malignancy during tumor progression.

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Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

Cited by 15 publications

References 47 publications

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

Classification of Cell-in-Cell Structures: Different Phenomena with Similar Appearance

Tumor malignancy by genetic transfer between cells forming cell-in-cell structures

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