Adopted neoplastic cells and the consequences of their existence.

A view that guides the bulk of cancer research and oncology posits that each neoplastic cell in a tumor is a genetic offspring of another neoplastic cell. Yet, analyzing tumors from transplant patients has revealed that some normal migratory cells adopt the phenotype of neoplastic cells without acquiring their genome, thus becoming what I suggest to call adopted neoplastic cells. This commentary reviews the evidence for the existence of adopted neoplastic cells, outlines the consequences of their presence, and discusses what kind of cells can be adopted, how, and why.

The problem of colliding networks and its relation to cell fusion and cancer.

Cell fusion, a process that merges two or more cells into one, is required for normal development and has been explored as a tool for stem cell therapy. It has also been proposed that cell fusion causes cancer and contributes to its progression. These functions rely on a poorly understood ability of cell fusion to create new cell types. We suggest that this ability can be understood by considering cells as attractor networks whose basic property is to adopt a set of distinct, stable, self-maintaining states called attractors. According to this view, fusion of two cell types is a collision of two networks that have adopted distinct attractors. To learn how these networks reach a consensus, we model cell fusion computationally. To do so, we simulate patterns of gene activities using a formalism developed to simulate patterns of memory in neural networks. We find that the hybrid networks can assume attractors that are unrelated to parental attractors, implying that cell fusion can create new cell types by nearly instantaneously moving cells between attractors. We also show that hybrid networks are prone to assume spurious attractors, which are emergent and sporadic network states. This finding means that cell fusion can produce abnormal cell types, including cancerous types, by placing cells into normally inaccessible spurious states. Finally, we suggest that the problem of colliding networks has general significance in many processes represented by attractor networks, including biological, social, and political phenomena.

Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.

The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.

Direct coupling of the cell cycle and cell death machinery by E2F.

Unrestrained E2F activity forces S phase entry and promotes apoptosis through p53-dependent and -independent mechanisms. Here, we show that deregulation of E2F by adenovirus E1A, loss of Rb or enforced E2F-1 expression results in the accumulation of caspase proenzymes through a direct transcriptional mechanism. Increased caspase levels seem to potentiate cell death in the presence of p53-generated signals that trigger caspase activation. Our results demonstrate that mitogenic oncogenes engage a tumour suppressor network that functions at multiple levels to efficiently induce cell death. The data also underscore how cell cycle progression can be coupled to the apoptotic machinery.

Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects.

A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.

Hard wiring of normal tissue-specific chromosome-wide gene expression levels is an additional factor driving cancer type-specific aneuploidies.

BACKGROUND: Many carcinomas have recurrent chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is not completely understood. METHODS: In this study, we looked at the frequency of chromosomal arm gains and losses in different cancer types from the The Cancer Genome Atlas (TCGA) and compared them to the mean gene expression of each chromosome arm in corresponding normal tissues of origin from the Genotype-Tissue Expression (GTEx) database, in addition to the distribution of tissue-specific oncogenes and tumor suppressors on different chromosome arms. RESULTS: This analysis revealed a complex picture of factors driving tumor karyotype evolution in which some recurrent chromosomal copy number reflect the chromosome arm-wide gene expression levels of the their normal tissue of tumor origin. CONCLUSIONS: We conclude that the cancer type-specific distribution of chromosomal arm gains and losses is potentially "hardwiring" gene expression levels characteristic of the normal tissue of tumor origin, in addition to broadly modulating the expression of tissue-specific tumor driver genes.

A virus causes cancer by inducing massive chromosomal instability through cell fusion.

Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6, 7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells.

A primate virus generates transformed human cells by fusion.

Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

The two cytochrome c species, DC3 and DC4, are not required for caspase activation and apoptosis in Drosophila cells.

In Drosophila, activation of the apical caspase DRONC requires the apoptotic protease-activating factor homologue, DARK. However, unlike caspase activation in mammals, DRONC activation is not accompanied by the release of cytochrome c from mitochondria. Drosophila encodes two cytochrome c proteins, Cytc-p (DC4) the predominantly expressed species, and Cytc-d (DC3), which is implicated in caspase activation during spermatogenesis. Here, we report that silencing expression of either or both DC3 and DC4 had no effect on apoptosis or activation of DRONC and DRICE in Drosophila cells. We find that loss of function mutations in dc3 and dc4, do not affect caspase activation during Drosophila development and that ectopic expression of DC3 or DC4 in Drosophila cells does not induce caspase activation. In cell-free studies, recombinant DC3 or DC4 failed to activate caspases in Drosophila cell lysates, but remarkably induced caspase activation in extracts from human cells. Overall, our results argue that DARK-mediated DRONC activation occurs independently of cytochrome c.

Gestational tumors as a model to probe reticulate evolution in human neoplasia.

Reticulate evolution, which involves the transfer of genes and other inheritable information between organisms, is of interest to a cancer researcher if only because "pirating" a trait can help a cell and its progeny adapt, survive, or take over much faster than by accumulating random mutations. However, despite being observed repeatedly in experimental models of neoplasia, reticulate evolution is assumed to be negligible in human cancer primarily because detecting gene transfer between the cells of the same genetic background can be difficult or impossible. This commentary suggests that gestational tumors, which are genetically distinct from the women who carry them, provide an opportunity to test whether reticulate evolution affects the development of human neoplasia.

Seeing how we smell.

PET allows noninvasive imaging of a variety of events in the body, including the activity of neuronal circuits in the brain that are involved in cognition and behaviors, by using radiotracers that detect relevant biological reactions. A major impediment to expanding PET applications to study the brain has been the lack of radiotracers that can identify and measure specific types of neurons or glial cells. In this issue of the JCI, Van de Bittner and colleagues describe a promising step toward solving this problem by identifying and describing a radiotracer, [11C]GV1-57, that appears to specifically label olfactory sensory neurons (OSNs), which are essential for olfaction (Figure 1). This tracer, if its specificity is confirmed, has the potential to become a prototype for future radiotracers that can identify other neuronal cell types and would allow visualization and in-depth characterization of these neurons and their genesis.

Confirming specificity of RNAi in mammalian cells.

RNA interference (RNAi) is a process of sequence-specific gene silencing. Recent advances in the understanding of RNAi have provided practical tools to silence gene expression in mammalian cells, opening new possibilities for studying the functions of genes and proteins. It is important to ensure that an observed effect of RNAi is due to silencing of the intended target. Indeed, it is possible that an siRNA may silence more than one messenger RNA that is homologous in the region complementary to the siRNA. Considering that we know little about how RNAi works in mammalian cells, other artifacts may be yet to be recognized. Thus, we suggest approaches to rescue the effect of RNAi by ectopically expressing the protein of interest. These approaches involve introducing silent mutations into the complementary DNA of the protein and targeting RNAi to the untranslated regions of the gene.

Components of the cell death machine and drug sensitivity of the National Cancer Institute Cell Line Panel.

PURPOSE: According to some studies, susceptibility of cells to anticancer drug-induced apoptosis is markedly inhibited by targeted deletion of genes encoding apoptotic protease activating factor 1 (Apaf-1) or certain caspases. Information about levels of these polypeptides in common cancer cell types and any possible correlation with drug sensitivity in the absence of gene deletion is currently fragmentary. EXPERIMENTAL DESIGN: Immunoblotting was used to estimate levels of Apaf-1 as well as procaspase-2, -3, -6, -7, -8, and -9 in the 60-cell-line panel used for drug screening by the National Cancer Institute. Sensitivity of the same lines to >80,000 compounds was determined with 48-hour sulforhodamine B binding assays. Additional 6-day assays were performed for selected agents. RESULTS: Levels of Apaf-1 and procaspases varied widely. Apaf-1 and procaspase-9, which are implicated in caspase activation after treatment of cells with various anticancer drugs, were detectable in all of the cell lines, with levels of Apaf-1 ranging from approximately 1 x 10(5) to 2 x 10(6) molecules per cell and procaspase-9 from approximately 5 x 10(3) to approximately 1.6 x 10(5) molecules per cell. Procaspase-8 levels ranged from 1.7 x 10(5) to 8 x 10(6) molecules per cell. Procaspase-3, a major effector caspase, varied from undetectable to approximately 1.6 x 10(6) molecules per cell. Correlations between levels of these polypeptides and sensitivity to any of a variety of experimental or conventional antineoplastic agents in either 2-day or 6-day cytotoxicity assays were weak at best. CONCLUSIONS: With the exception of caspase-3, all of the components of the core cell-death machinery are expressed in all of the cell lines examined. Despite variations in expression, levels of any one component are not a major determinant of drug sensitivity in these cells in vitro.

A sense of life: computational and experimental investigations with models of biochemical and evolutionary processes.

We collaborate in a research program aimed at creating a rigorous framework, experimental infrastructure, and computational environment for understanding, experimenting with, manipulating, and modifying a diverse set of fundamental biological processes at multiple scales and spatio-temporal modes. The novelty of our research is based on an approach that (i) requires coevolution of experimental science and theoretical techniques and (ii) exploits a certain universality in biology guided by a parsimonious model of evolutionary mechanisms operating at the genomic level and manifesting at the proteomic, transcriptomic, phylogenic, and other higher levels. Our current program in "systems biology" endeavors to marry large-scale biological experiments with the tools to ponder and reason about large, complex, and subtle natural systems. To achieve this ambitious goal, ideas and concepts are combined from many different fields: biological experimentation, applied mathematical modeling, computational reasoning schemes, and large-scale numerical and symbolic simulations. From a biological viewpoint, the basic issues are many: (i) understanding common and shared structural motifs among biological processes; (ii) modeling biological noise due to interactions among a small number of key molecules or loss of synchrony; (iii) explaining the robustness of these systems in spite of such noise; and (iv) cataloging multistatic behavior and adaptation exhibited by many biological processes.

What are the hallmarks of cancer?

The seminal article by Douglas Hanahan and Robert Weinberg on the hallmarks of cancer is 10 years old this year and its contribution to how we see cancer has been substantial. But, in embracing this view, have we lost sight of what makes cancer cancer?

V-fusion: a convenient, nontoxic method for cell fusion.

Cell-to-cell fusion (cell fusion) is a fundamental biological process that also has been used as a versatile experimental tool to dissect a variety of cellular mechanisms, including the consequences of cell fusion itself, and to produce cells with desired properties, such as hybridomas and reprogrammed progenitors. However, current methods of cell fusion are not satisfactory because of their toxicity, inefficiency, or lack of flexibility. We describe a simple, versatile, scalable, and nontoxic approach that we call V-fusion, as it is based on the ability of the vesicular stomatitis virus G protein (VSV-G), a viral fusogen of broad tropism, to become rapidly and reversibly activated. We suggest that this approach will benefit a broad array of studies that investigate consequences of cell fusion or use cell fusion as an experimental tool.