Ancestral gene regulatory networks drive cancer

Bussey, Kimberly J.; Cisneros, Luis; Lineweaver, Charles H.; Davies, Paul

doi:10.1073/pnas.1706990114

Cited by 57 publications

(43 citation statements)

References 14 publications

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“…The resulting cells will assume a survival strategy that is inherited from primitive ancestors. This agrees with that cancer is driven by ancestral gene regulatory networks, and cancer genes are mostly conserved in unicellular and basal species of multicellular organisms [48][49][50]. Cancer cell metabolism is characteristic of anaerobic processes, which were the metabolic style of the last common ancestor of unicellular and multicellular organisms in an oxygen-de cient environment in about 600 million years ago.…”

Section: Discussionsupporting

confidence: 85%

Neural stemness contributes to cell tumorigenicity

Zhang

Shi

et al. 2020

Preprint

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Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

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Section: Discussionsupporting

confidence: 85%

Neural stemness contributes to cell tumorigenicity

Zhang

Shi

et al. 2020

Preprint

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“…However, our view merely proposes that the usage of mitochondria-dependent signaling functions evolutionary rooted in the bacterial origin of mitochondria might be considered a primary cause of non-genetic distortions in the manner of Waddingtonian non-CSC versus CSC cellular states (attractors), which might be amenable to broadspectrum cancer therapies capable of mitochondrially tackling CSC-driven inter-and intra-tumor heterogeneity [9]. Our mitostemness proposal is consistent with a number of descriptions in which the determination of cell fate involves the asymmetric distribution of certain mitochondrial controllers into CSC-like cell entities [84][85][86][87][88][89]. Indeed, our proposal complements the view that changes in intracellular, intercellular, and extracellular mitochondrial traffic [90][91][92][93][94] appear to ensure the functional endurance of mitochondria in the tumor-initiating and drug-resistant subpopulation of CSC.…”

Section: Mitostemness: Echoes From the Past?supporting

confidence: 82%

“…The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena such as those governing the retention versus loss of cancer stemness would be viewed as a continuation of the atavism hypothesis of cancer, which states that tumor development and metastasis relies on the functional disruption of genes that sustain multicellularity upon reactivation of primitive transcriptional programs that evolved in the earliest single-celled organisms [80][81][82]. We acknowledge that an ever-growing number of studies begin to support the notion that the high degree of robustness and plasticity occurring via activation of unicellular networks might confer CSClike tumor adaptability to drug exposure [83][84][85]. However, our view merely proposes that the usage of mitochondria-dependent signaling functions evolutionary rooted in the bacterial origin of mitochondria might be considered a primary cause of non-genetic distortions in the manner of Waddingtonian non-CSC versus CSC cellular states (attractors), which might be amenable to broadspectrum cancer therapies capable of mitochondrially tackling CSC-driven inter-and intra-tumor heterogeneity [9].…”

Section: Mitostemness: Echoes From the Past?mentioning

confidence: 99%

Mitostemness

et al. 2018

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Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation. Mitostemness traits, namely mitonuclear communication, mitoproteome components, and mitochondrial fission/fusion dynamics, can be therapeutically exploited to target the CSC state. We briefly review the pre-clinical evidence of action of investigational compounds on mitostemness traits and discuss ongoing strategies to accelerate the clinical translation of new mitostemness drugs. The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena may open up a new therapeutic dimension against life-threatening CSCs. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.

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“…Despite highly diverse molecular and clinical manifestations, one common aspect points to the key: in carcinogenic transformation (Yamasaki et al, 1995;Ruch and Trosko, 2001), cells become isolated from the physiological signals that bind them into unified networks (the essential role of bioelectricity in this process is discussed in the next section). In the absence of global cues, they revert to their unicellular past, when their behaviors were aimed at optimizing the future of just one cell: proliferate as much as possible, and travel to whatever location affords the best local environment for nutrients and expansion (Davies and Lineweaver, 2011;Bussey et al, 2017;Zhou et al, 2018a). This is a breakdown of multicellularity and highlights the fact that the scale of the structure which cells work to maintain can change rapidlyfrom cooperation toward an entire organ system or body to the level of a single cell.…”

Section: Multicellularity Vs Cancer: the Shifting Boundary Of The Selfmentioning

confidence: 99%

The Computational Boundary of a “Self”: Developmental Bioelectricity Drives Multicellularity and Scale-Free Cognition

2019

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All epistemic agents physically consist of parts that must somehow comprise an integrated cognitive self. Biological individuals consist of subunits (organs, cells, and molecular networks) that are themselves complex and competent in their own native contexts. How do coherent biological Individuals result from the activity of smaller sub-agents? To understand the evolution and function of metazoan creatures' bodies and minds, it is essential to conceptually explore the origin of multicellularity and the scaling of the basal cognition of individual cells into a coherent larger organism. In this article, I synthesize ideas in cognitive science, evolutionary biology, and developmental physiology toward a hypothesis about the origin of Individuality: "Scale-Free Cognition." I propose a fundamental definition of an Individual based on the ability to pursue goals at an appropriate level of scale and organization and suggest a formalism for defining and comparing the cognitive capacities of highly diverse types of agents. Any Self is demarcated by a computational surface -the spatio-temporal boundary of events that it can measure, model, and try to affect. This surface sets a functional boundarya cognitive "light cone" which defines the scale and limits of its cognition. I hypothesize that higher level goal-directed activity and agency, resulting in larger cognitive boundaries, evolve from the primal homeostatic drive of living things to reduce stress -the difference between current conditions and life-optimal conditions. The mechanisms of developmental bioelectricity -the ability of all cells to form electrical networks that process informationsuggest a plausible set of gradual evolutionary steps that naturally lead from physiological homeostasis in single cells to memory, prediction, and ultimately complex cognitive agents, via scale-up of the basic drive of infotaxis. Recent data on the molecular mechanisms of pre-neural bioelectricity suggest a model of how increasingly sophisticated cognitive functions emerge smoothly from cell-cell communication used to guide embryogenesis and regeneration. This set of hypotheses provides a novel perspective on numerous phenomena, such as cancer, and makes several unique, testable predictions for interdisciplinary research that have implications not only for evolutionary developmental biology but also for biomedicine and perhaps artificial intelligence and exobiology.

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Ancestral gene regulatory networks drive cancer

Cited by 57 publications

References 14 publications

Neural stemness contributes to cell tumorigenicity

Neural stemness contributes to cell tumorigenicity

Mitostemness

The Computational Boundary of a “Self”: Developmental Bioelectricity Drives Multicellularity and Scale-Free Cognition

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