The shock of being united and symphiliosis

Lazebnik, Yuri

doi:10.4161/cc.29704

Cited by 16 publications

(17 citation statements)

References 101 publications

(160 reference statements)

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“…In many cases, this appeared as “sheets” of chromatin. This poorly understood process of DNA handling or reconciliation has been referred to as “symphiliosis [ 37 ] (see Discussion ). In many cells, smaller “clumps” of condensed chromatin were observed in the cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the route by which polyploidy occurs may have a major impact on its consequences, as has recently been hypothesized based on lessons from plants [ 37 ]. There, polyploid cells arising as “Allopolyploids” have far different characteristics than those arising as “autopolyploids” [ 27 , 37 ]. When fusion of 2 different cell types occurs, two distinct cellular programs need to be merged somehow.…”

Section: Discussionmentioning

confidence: 99%

“…When fusion of 2 different cell types occurs, two distinct cellular programs need to be merged somehow. This process has been referred to symphiliosis, the process of intracellular reconciliation [ 37 ]. This suddenly produces new clones with emergent phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

et al. 2015

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BackgroundWhile the morbidity and mortality from cancer are largely attributable to its metastatic dissemination, the integral features of the cascade are not well understood. The widely accepted hypothesis is that the primary tumor microenvironment induces the epithelial-to-mesenchymal transition in cancer cells, facilitating their escape into the bloodstream, possibly accompanied by cancer stem cells. An alternative theory for metastasis involves fusion of macrophages with tumor cells (MTFs). Here we culture and characterize apparent MTFs from blood of melanoma patients.MethodsWe isolated enriched CTC populations from peripheral blood samples from melanoma patients, and cultured them. We interrogated these cultured cells for characteristic BRAF mutations, and used confocal microscopy for immunophenotyping, motility, DNA content and chromatin texture analyses, and then conducted xenograft studies using nude mice.FindingsMorphologically, the cultured MTFs were generally large with many pseudopod extensions and lamellipodia. Ultrastructurally, the cultured MTFs appeared to be macrophages. They were rich in mitochondria and lysosomes, as well as apparent melanosomes. The cultured MTF populations were all heterogeneous with regard to DNA content, containing aneuploid and/or high-ploidy cells, and they typically showed large sheets (and/or clumps) of cytoplasmic chromatin. This cytoplasmic DNA was found within heterogeneously-sized autophagic vacuoles, which prominently contained chromatin and micronuclei. Cultured MTFs uniformly expressed pan-macrophage markers (CD14, CD68) and macrophage markers indicative of M2 polarization (CD163, CD204, CD206). They also expressed melanocyte-specific markers (ALCAM, MLANA), epithelial biomarkers (KRT, EpCAM), as well as the pro-carcinogenic cytokine MIF along with functionally related stem cell markers (CXCR4, CD44). MTF cultures from individual patients (5 of 8) contained melanoma-specific BRAF activating mutations. Chromatin texture analysis of deconvoluted images showed condensed DNA (DAPI-intense) regions similar to focal regions described in stem cell fusions. MTFs were readily apparent in vivo in all human melanomas examined, often exhibiting even higher DNA content than the cultured MTFs. When cultured MTFs were transplanted subcutaneously in nude mice, they disseminated and produced metastatic lesions at distant sites.Conclusions and HypothesisApparent MTFs are present in peripheral blood of patients with cutaneous melanomas, and they possess the ability to form metastatic lesions when transplanted into mice. We hypothesize that these MTFs arise at the periphery of primary tumors in vivo, that they readily enter the bloodstream and invade distant tissues, secreting cytokines (such as MIF) to prepare “niches” for colonization by metastasis initiating cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

et al. 2015

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“…When fusion of 2 different cell types occurs, two distinct cellular programs need to be merged. This process has been referred to as symphiliosis, the process of intracellular reconciliation [ 108 ], which suddenly produces new clones with emergent phenotypes. Cancer cells can transduce adjacent TME cells in vivo, and it has been suggested that in vivo fusion discloses genes implicated in tumor progression [ 109 ].…”

Section: Discussionmentioning

confidence: 99%

"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

et al. 2017

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Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal adenocarcinoma (PDAC) patients. The MTFs were generally aneuploidy, and immunophenotypic characterizations showed that the MTFs express markers characteristic of PDAC and stem cells, as well as M2-polarized macrophages. Single cell RNASeq analyses showed that the MTFs express many transcripts implicated in cancer progression, LINE1 retrotransposons, and very high levels of several long non-coding transcripts involved in metastasis (such as MALAT1). When cultured MTFs were transplanted orthotopically into mouse pancreas, they grew as obvious well-differentiated islands of cells, but they also disseminated widely throughout multiple tissues in “stealth” fashion. They were found distributed throughout multiple organs at 4, 8, or 12 weeks after transplantation (including liver, spleen, lung), occurring as single cells or small groups of cells, without formation of obvious tumors or any apparent progression over the 4 to 12 week period. We suggest that MTFs form continually during PDAC development, and that they disseminate early in cancer progression, forming “niches” at distant sites for subsequent colonization by metastasis-initiating cells.

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“…Recent work has demonstrated that these diversifying processes engender the establishment of genetically rich cell communities upon which natural selection acts (Stephens et al 2011;NikZainal et al 2012a,b;Baca et al 2013). The recognition of most of these processes challenges the view that cancer evolution is simply a process of gradual serial mutation accumulation, arguing instead that punctuated or saltational evolutionary trajectories can also be important (Baca et al 2013;Lazebnik 2014). Several dramatic examples of the types of genome modification that have been reported in cancer evolution include the following:…”

Section: Box 1 Engines Of Genome Diversificationmentioning

confidence: 99%

Genome management and mismanagement—cell-level opportunities and challenges of whole-genome duplication

Yant

Bomblies

2015

Genes Dev.

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Whole-genome duplication (WGD) doubles the DNA content in the nucleus and leads to polyploidy. In whole-organism polyploids, WGD has been implicated in adaptability and the evolution of increased genome complexity, but polyploidy can also arise in somatic cells of otherwise diploid plants and animals, where it plays important roles in development and likely environmental responses. As with whole organisms, WGD can also promote adaptability and diversity in proliferating cell lineages, although whether WGD is beneficial is clearly context-dependent. WGD is also sometimes associated with aging and disease and may be a facilitator of dangerous genetic and karyotypic diversity in tumorigenesis. Scaling changes can affect cell physiology, but problems associated with WGD in large part seem to arise from problems with chromosome segregation in polyploid cells. Here we discuss both the adaptive potential and problems associated with WGD, focusing primarily on cellular effects. We see value in recognizing polyploidy as a key player in generating diversity in development and cell lineage evolution, with intriguing parallels across kingdoms.

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The shock of being united and symphiliosis

Cited by 16 publications

References 101 publications

Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

Genome management and mismanagement—cell-level opportunities and challenges of whole-genome duplication

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