Cell-cell fusion in cancer: The next cancer hallmark?

Shultes, Paulameena V.; Weaver, Davis T.; Tadele, Dagim S.; Barker-Clarke, Rowan J.; Scott, Jacob G.

doi:10.1016/j.biocel.2024.106649

Cited by 3 publications

References 137 publications

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Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo

Druzhkova,

Potapov,

Ignatova

et al. 2024

Sci Rep

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Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell’s ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency.

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Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo

Druzhkova,

Potapov,

Ignatova

et al. 2024

Sci Rep

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Cell-Cell Fusion in NSCLC Confers a Fitness Benefit Under Drug Selection

Shultes,

Tadele,

Durmaz

et al. 2024

Preprint

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Cell-cell fusion has been implicated in various physiological and pathological processes, including cancer progression. This study investigated the role of cell-cell fusion in non-small cell lung cancer (NSCLC), focusing on its contribution to chemoresistance and tumor evolution. By co-culturing drug-sensitive and drug-resistant NSCLC cell lines, we observed spontaneous cell-cell fusion events, particularly under gefitinib selection. These fused cells exhibited enhanced fitness and a higher degree of chemoresistance compared to parental lines across a panel of 12 chemotherapeutic agents. Further analysis, including fluorescence imaging and cell cycle analysis, confirmed nuclear fusion and increased DNA content in the fused cells. Bulk RNA sequencing revealed genomic heterogeneity in fused cells, including enrichment of gene sets associated with cell cycle progression and epithelial-mesenchymal transition, hallmarks of cancer malignancy. These findings demonstrate that cell-cell fusion contributes significantly to therapeutic resistance and the promotion of aggressive phenotypes in NSCLC, highlighting its potential as a therapeutic target.

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Mapping cell-cell fusion at single-cell resolution

Gardner,

Zheng,

Howland

et al. 2024

Preprint

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Cell-cell fusion is a tightly controlled process in the human body known to be involved in fertilization, placental development, muscle growth, bone remodeling, and viral response. Fusion between cancer cells results first in a whole-genome doubled state, which may be followed by the generation of aneuploidies; these genomic alterations are known drivers of tumor evolution. The role of cell-cell fusion in cancer progression and treatment response has been understudied due to limited experimental systems for tracking and analyzing individual fusion events. To meet this need, we developed a molecular toolkit to map the origins and outcomes of individual cell fusion events within a tumor cell population. This platform, ClonMapper Duo (‘CMDuo’), identifies cells that have undergone cell-cell fusion through a combination of reporter expression and engineered fluorescence-associated index sequences paired to random barcode sets. scRNA-seq of the indexed barcodes enables the mapping of each set of parental cells and fusion progeny throughout the cell population. In triple negative breast cancer cells CMDuo uncovered subclonal transcriptomic hybridization and unveiled distinct cell-states which arise in direct consequence of homotypic cell-cell fusion. CMDuo is a platform that enables mapping of cell-cell fusion events in high-throughput single cell data and enables the study of cell fusion in disease progression and therapeutic response.

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Cell-cell fusion in cancer: The next cancer hallmark?

Cited by 3 publications

References 137 publications

Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo

Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo

Cell-Cell Fusion in NSCLC Confers a Fitness Benefit Under Drug Selection

Mapping cell-cell fusion at single-cell resolution

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