Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival

Gast, Charles E.; Silk, Alain D.; Zarour, Luai; Riegler, Lara; Burkhart, Joshua G.; Gustafson, Kyle T.; Parappilly, Michael; Roh-Johnson, Minna; Goodman, James R.; Olson, Brennan; Schmidt, Mark; Swain, John; Davies, Paige S.; Shasthri, Vidya; Iizuka, Shinji; Flynn, Patrick; Watson, Spencer S.; Korkola, James E.; Courtneidge, Sara A.; Fischer, Jared M.; Jaboin, Jerry J.; Billingsley, Kevin G.; Lopez, Charles D.; Burchard, Julja; Gray, Joe W.; Coussens, Lisa M.; Sheppard, Brett C.; Wong, Melissa H.

doi:10.1126/sciadv.aat7828

Cited by 243 publications

(471 citation statements)

References 54 publications

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“…Fusion between cancer cells and nonmalignant cells such as macrophages, endothelial cells, and epithelial cells, and very rare events of fusion between nonmalignant cells, have been suggested to promote the formation and progression of tumors (12,13,40). Fusion of cancer cells with leukocytes generates cells exhibiting increased metastatic behavior and the number of these fusion hybrids in peripheral blood of human patients with cancer correlates with disease stage (41). On the other hand, it has been suggested that fusion between cancer cells could suppress their invasive phenotype and that Syn1 expression could be used as a positive prognostic marker (42).…”

Section: Formation Of Multinucleated Prostate Cancer Cells Depends Onmentioning

confidence: 99%

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Uygur

Leikina

Melikov

et al. 2019

Molecular Cancer Research

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Poorly understood interactions with nonmalignant cells within the tumor microenvironment play an important role in cancer progression. Here, we explored interactions between prostate cancer and muscle cells that surround the prostate. We found that coculturing of prostate cancer cells with skeletal or smooth muscle cells expands the subpopulations of cancer cells with features characteristic of cancer stem-like cells, including anchorage-independent growth, elevated CD133 expression, and drug resistance. These changes in the properties of cancer cells depend on: (i) the muscle cell-induced increases in the concentrations of interleukins 4 and 13; (ii) the cytokine-induced upregula-tion of the expression of syncytin 1 and annexin A5; and (iii) cancer cell fusion. In human prostate cancer tissues, expression of syncytin 1 and annexin A5, proteins that we found to be required for the cell fusion, positively correlated with the cancer development suggesting that these proteins can be used as biomarkers to evaluate cancer progression and potential therapeutic targets. Implications:The discovered effects of muscle cells on prostate cancer cells reveal a novel and specific pathway by which muscle cells in the microenvironment of prostate cancer cells promote cell fusion and cancer progression.

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Section: Formation Of Multinucleated Prostate Cancer Cells Depends Onmentioning

confidence: 99%

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Uygur

Leikina

Melikov

et al. 2019

Molecular Cancer Research

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“…In this report we present the generation and characterization of a CDK ratiometric biosensor based on the CDK2 phosphorylation domain of human DNA Helicase B (DHB) (Hahn et al, 2009;Spencer et al, 2013) capable of distinguishing all interphase cell cycle states throughout the life cycle of C. elegans, including the G0 phase of the cell cycle. In mammalian cell culture, DHB as a CDK2 biosensor has been a useful tool to visualize the difference between proliferative and quiescent cells in asynchronous cell populations (Arora et al, 2017;Cappell et al, 2016;Gast et al, 2018;Gookin et al, 2017;Miller et al, 2018;Moser et al, 2018;Overton et al, 2014;Spencer et al, 2013;. This has prompted researchers to define a new cell cycle restriction point as a bifurcation point immediately following mitotic exit based on CDK2 activity, with proliferative cells exiting at a CDK2 increasing (CDK2 inc ) state and quiescent cells exiting at a CDK2 low (CDK2 low ) state (Spencer et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Visualizing the metazoan proliferation-terminal differentiation decisionin vivo

Kohrman

Adikes

Martinez

et al. 2019

Preprint

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During organismal development, differential regulation of the cell cycle is critical to many cell biological processes, including cell fate specification and differentiation. While the mechanisms of cell cycle regulation are well studied, how control of the cell cycle is linked to differentiated cellular behavior remains poorly understood, mostly due to our inability to directly and precisely measure cell cycle state. In order to characterize cell cycle state live, we adapted a cyclindependent kinase (CDK) biosensor for in vivo use in the roundworm nematode, Caenorhabditis elegans. The CDK biosensor measures the cytoplasmic-to-nuclear localization of a portion of human DNA Helicase B (DHB) fused to a fluorescent protein to assess cell cycle state. The dynamic localization of DHB results from phosphorylation of the biosensor by CDKs, thereby allowing for quantitative assessment of cell cycle state. We demonstrate here the use of this biosensor to quantify lineage-specific differences between cycling cells and to examine the proliferation-differentiation decision. Unlike other live cell imaging tools (e.g., FUCCI), we show that DHB can be used to distinguish between actively cycling cells in the G1 phase of the cell cycle and terminally differentiated cells exited in G0. Thus, we provide here a new resource to study the control and timing of the metazoan cell cycle during cell fate specification and differentiation.

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“…In contrast to the EMT, the macrophage fusion hybrid hypothesis posits that metastasis arises from macrophages either directly or indirectly from the fusion of macrophages with neoplastic cells (109,(114)(115)(116)(117). The metastatic breast cancer cell, like many metastatic cancer cells, expresses characteristics of myeloid cells and macrophages (109,114,(118)(119)(120)(121)(122)(123)(124)(125).…”

Section: Origin Of Metastasismentioning

confidence: 99%

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

et al. 2020

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Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

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Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival

Abstract: Peripheral blood MФ–cancer cell fusion hybrids identified in cancer patients correlate with disease stage and overall survival.

Cited by 243 publications

References 54 publications

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Visualizing the metazoan proliferation-terminal differentiation decisionin vivo

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

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