Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells

Fernandes, Clara; Prabhu, Priyanka; Juvale, Kapil; Suares, Divya; Mayur, Y.C.

doi:10.1016/j.drudis.2019.05.024

Cited by 22 publications

(22 citation statements)

References 84 publications

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“…This intriguing hypothesis remained controversial during the 20th century when the somatic mutation theory of carcinogenesis was the dominant force driving cancer research. In the past decade, however, a significant number of reports have underscored the importance of cell fusion in tumor progression and therapy resistance in a wide range of malignancies (e.g., [136][137][138][139][140][141][142][143][144][145]). In a recent study reported by Gast and associates [144], for example, cancer cell-leukocyte hybrids were detected in peripheral blood of cancer patients, and the numbers of such hybrids in the patient's blood correlated with disease stage and predicted overall survival.…”

Section: The Role Of Cancer Cell Fusion In Metastasis and Therapy Resmentioning

confidence: 99%

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Mirzayans

Murray

2020

IJMS

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A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century.

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Section: The Role Of Cancer Cell Fusion In Metastasis and Therapy Resmentioning

confidence: 99%

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Mirzayans

Murray

2020

IJMS

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“…4 University of Bordeaux, 146 rue Léo Saignat, F-33000 Bordeaux, France. 5 Department of Biopathology, Bergonie Institute, 229 cours de l'Argonne, F-33076 Bordeaux, France. 6 CNRS UMR 5164, 33000 Bordeaux, France.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Cell fusion is a normal physiological event that plays a critical role in fertilization, placentation, myogenesis, osteogenesis, wound healing and tissue regeneration [1][2][3][4]. In addition, it is strongly suggested to be a tumor inception contributor, progression and heterogeneity [5]. Several studies have demonstrated the presence of hybrid cells in human cancers, in some cases comprising up to 40% of tumors [6].…”

Section: Introductionmentioning

confidence: 99%

Cell fusion enhances energy metabolism of mesenchymal tumor hybrid cells to sustain their proliferation and invasion

et al. 2021

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Background Cell-to-cell fusion is emerging as a key element of the metastatic process in various cancer types. We recently showed that hybrids made from the spontaneous merging of pre-malignant (IMR90 E6E7, i.e. E6E7) and malignant (IMR90 E6E7 RST, i.e. RST) mesenchymal cells recapitulate the main features of human undifferentiated pleomorphic sarcoma (UPS), with a highly rearranged genome and increased spreading capacities. To better characterize the intrinsic properties of these hybrids, we investigated here their metabolic energy profile compared to their parents. Results Our results unveiled that hybrids harbored a Warburg-like metabolism, like their RST counterparts. However, hybrids displayed a much greater metabolic activity, enhancing glycolysis to proliferate. Interestingly, modifying the metabolic environmental conditions through the use of 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR), an activator of the 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), specifically reduced the growth of hybrids, and also abrogated the invasive capacity of hybrids displaying enhanced glycolysis. Furthermore, AICAR efficiently blocked the tumoral features related to the aggressiveness of human UPS cell lines. Conclusion Altogether, our findings strongly suggest that hybrids rely on higher energy flux to proliferate and that a drug altering this metabolic equilibrium could impair their survival and be potentially considered as a novel therapeutic strategy.

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“…The provocative hypothesis that tumor cells fuse with white blood cells to migrate and escape the immune surveillance to grow to metastases in other organs, was developed more than 100 years ago [9]. Recently several groups have proposed cancer cell fusions, and in particular leukocyte-tumor cell fusions, to have potential significant roles in tumor progression, cancer metastasis, and chemotherapy resistance in solid cancers [10,11]. Molecular mechanisms of cellular fusion have been suggested, and intercellular connections (e. g., via tunneling nanotubes (TNTs)) might play a role in partial and permanent cell fusions [12,13].…”

Section: Introductionmentioning

confidence: 99%

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

Manjunath

Porciani

Mitchem

et al. 2020

IJMS

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Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.

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Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells

Cited by 22 publications

References 84 publications

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Cell fusion enhances energy metabolism of mesenchymal tumor hybrid cells to sustain their proliferation and invasion

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

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