Phenotypic Switching: Implications in Biology and Medicine

WARNING!!! DUMMY ENTRY
	Phenotypic Switching
Phenotypic Switching
Copyright
Contents
List of contributors
Preface
	Introduction
	Background: Lamarck and Darwin
	Woltereck and the reaction norm
	Waddington, canalization and genetic assimilation
	Behavior; the Baldwin effect
	Domestication
	Developmental noise
	Phenotypic noise and phenotypic plasticity
	Cancer
	Summing up
	Acknowledgments
Summaries of contributions
Acknowledgments
1 The fundamentals of phenotypic plasticity
	Introduction
	Phenotypic plasticity at an intracellular level: macromolecules, pathways, and organelles
	Phenotypic plasticity at a cellular level: Implications in development, homeostasis, and disease
	Phenotypic plasticity at the organismal level
	Conclusion
	Acknowledgment
	References
2 Rethinking the role of chance in the explanation of cell differentiation
	Introduction
	Noise in gene expression: a descriptive analysis
	What, actually, is noise?
	From noise to chance as explanatory
	Chance in immunology: an example to follow
	A positive view of chance: main features and theoretical advantages
	Three reasons for biological explanations in terms of chance
	Conclusion: Chance and the reductionism/antireductionism debate
	Acknowledgments
	References
3 Random walk across the epigenetic landscape
	Concepts
	Historical origins
	The epigenetic landscape
	A new conceptual framework
	Putting together the pieces of the puzzle to build a new operative model
	Conclusion
	Acknowledgments
	References
4 Manoeuvring protein functions and functional levels by structural excursions
	Moonlighting proteins
	Functional switch mediated by protein–protein interactions
	Modulation of protein function by oligomerization
	Influence of domain association on protein function
	Modulation of protein function by posttranslational modifications
	Silent mutation tunes gene function
		Synonymous mutations dictate gene splicing
		Synonymous mutations regulate folding of mRNA secondary structure
		Synonymous mutations impair the interactions of mRNA with RNA-binding proteins and miRNAs
		Synonymous mutations modulate cotranslational folding
	Conclusion
	Acknowledgments
	Abbreviations
	References
5 Prion-mediated phenotypic diversity in fungi
	Introduction
	Prion formation and loss
	Prion propagation and transmission in the fungal cell
	Prion-mediated phenotypes
		[PSI+]/Sup35: regulating the decoding of stop codons and more
		[MOT3+]/Mot3: controlling multicellularity in response to environmental triggers
		[SWI+]/Swi1: an impact on global transcriptional regulation
		[GAR+]/Pma1/Std1: broadening the choice of sugars
	Conformational diversity generates phenotypic diversity
	Concluding remarks
	Acknowledgments
	References
6 Bistability in virus–host interaction networks underlies the success of hepatitis C treatments
	Introduction
	Bistability in the interferon signaling network
		Interferons and HCV infection
		HCV induces bistability in the interferon signaling network
		Phenotypic heterogeneity in interferon responsiveness
	Phenotypic heterogeneity, viral kinetics, and treatment outcomes
		Interferon-based treatment outcome
		Leveraging endogenous interferon responsiveness to improve DAA treatments
	Potential considerations and strategies for optimizing DAA treatments
		Mutational pathways of resistance to DAA-based treatments
		Posttreatment cure
		Natural outcomes of HCV infection
	Concluding remarks
	Acknowledgments
	References
7 Quantifying Waddington landscapes, paths, and kinetics of cell fate decision making of differentiation/development
	Introduction
	Potential and flux landscape theory of cell fate decision of differentiation and reprograming
		Potential and flux as the driving force for stem cell differentiation and development
		Optimal paths for quantifying the differentiation/development and reprograming processes
		Kinetic rates of differentiation/development and reprograming cell fate decision-making processes
	Quantifying Waddington landscape and paths for differentiation/development
		Gene regulatory motif circuit determining the differentiation
		Cell fate decision for differentiation and reprograming through regulations
		Quantified Waddington landscape and paths for development/differentiation
		Epigenetics, heterogeneity, and plasticity
		Identifying key factors of cell fate decision making in differentiation/development
	Discussions on critical issues of cell fate decision making of differentiation and development
		Cell fate decision-making dynamics of differentiation/development is not only determined by the landscape but also by the c...
		The differences of the original Waddington landscape and quantified landscape for cell fate decision making in differentiat...
		Origins of the bifurcations and phase transitions of cell fate decision making of differentiation/development
		Time arrow and mechanism of irreversibility originating from the curl flux breaking the detailed balance
		Heterogeneity from epigenetics
		Quantifications of transition states, speed, and optimal paths of cell fate decision making of differentiation and reprogra...
		Transition states or intermediate states?
		Discrete paths versus continuous paths
	Acknowledgment
	References
8 The physics of cell fate
	Introduction
	The “physical laws” of cell fate dynamics
	Statistical mechanics of cell state dynamics
	Universality in cell biology
	Critique and outlook
	Conclusions
	References
9 Disentangling the environmentally induced and stochastic developmental components of phenotypic variation
	Introduction
	Considerations on phenotypic, genetic, environmentally induced, and stochastic developmental variations
	Occurrence of environmentally induced variation and stochastic developmental variation in the kingdoms of life
	Determination of stochastic developmental variation in laboratory experiments
	Disentangling genetic variation, environmentally induced variation, and stochastic developmental variation in the laboratory
	Disentangling genetic variation, environmentally induced variation, and stochastic developmental variation in field studies
	Disentangling genetic variation plus environmentally induced variation from stochastic developmental variation by mathemati...
	Identification of the molecular mechanisms underlying environmentally induced variation and stochastic developmental variation
	The marbled crayfish as a promising model for investigating the nongenetic components of phenotypic variation
	Conclusions
	Acknowledgments
	References
10 The evolution of cell differentiation in animals: biomolecular condensates as amplification hubs of inherent cell functions
	Introduction
	Metazoan-specific modes of transcriptional regulation
	Beta-catenin, Grainyhead-like and the role of multicellularity in the evolution of differentiation
	Inherent cell functions in the origin of differentiation
	Conclusion: Prolific cell differentiation as a metazoan evolutionary innovation
	Abbreviations
	References
11 Phenotypic switching and its evolutionary consequences
	Evolution and the principle of inheritance
	Molecular basis and examples of epigenetically determined phenotypic switching
	Evolutionary consequences of phenotypic switching
	Acknowledgments
	References
12 Cell-state organization by exploratory sloppy dynamics
	Introduction
	Experimental approach: cell adaptation to an unforeseen challenge
	Implications of the yeast adaptation experiments
		The exploratory dynamics of cell-state organization
		The living cell as a sloppy dynamical system
	Summary and open issues
	Acknowledgments
	References
13 Emergence of metabolic heterogeneity in cell populations: lessons from budding yeast
	Introduction: cell state heterogeneity in isogenic microbial populations
	Metabolic heterogeneity and spatial organization within yeast colonies
		The idea of a threshold, controlling resource
	General considerations on the manifestation of multiple cellular states at the population level
		Case 1: When growth is much faster than switching, such that one can ignore the latter
		Case 2: When switching is much faster than growth, such that one can ignore the latter
		Case 3: Both switching and growth have to be taken into account
	Cell-state heterogeneity of yeast in a well-mixed chemostat
	Discussion
	Acknowledgments
	Appendix
		Case 1: When growth is much faster than switching, such that one can ignore the latter
		Case 2: When switching is much faster than growth, such that one can ignore the latter
		Case 3: Both switching and growth have to be taken into account
	References
14 Stochastic phenotypic switching in endothelial cell heterogeneity
	Introduction
		From genes to phenotypic plasticity
		Biological noise meets phenotypic plasticity
			Biological noise in developmental plasticity
			Biological noise in response to environmental change
			Stochastic phenotype switching and cellular memory
		Is biological noise-mediated heterogeneity adaptive?
	Noise-mediated endothelial cell heterogeneity in vivo
		Dynamic heterogeneity of vWF expression in vivo
		Dynamic vWF mosaicism in vitro is driven by biological noise
		Epigenetic control of vWF expression and heterogeneity
		Loss of vWF-positive cells from mosaic capillary beds correlates with profound impairment of tissue function
			Loss of vWF mosaic expression in heart capillaries
			Loss of vWF mosaic expression in brain capillaries
	Discussion—implications of biological noise-driven bed hedging as an adaptive trait
	References
15 Regulation of phenotypic plasticity from the perspective of evolutionary developmental biology
	Introduction to phenotypic plasticity
	What are polyphenisms?
	Regulation of developmental plasticity
		Sensors
			Neural sensors
			Epigenetic regulation of polyphenisms
		Integrators
			The central nervous system and hormones
			Endocrine integrators of phenotypic plasticity in vertebrates
			Endocrine integrators of phenotypic plasticity in insects
		Effectors
			What are effectors?
			Effectors of plastic growth
			Effectors involved in plastic patterning
			Metamorphosis
	Nonadaptive plasticity and the evolution of robustness
	Plasticity as an adaptation
	Reaction norms and allometries
	Are polyphenisms reaction norms?
	Evolution via phenotypic plasticity
	The role of cryptic genetic variation in genetic accommodation
		The role of robustness and homeostasis in speciation
	Model of genetic accommodation
		The epigenetic watershed
	Conclusions
	References
16 Phenotypic plasticity and the origins of novelty
	Introduction
	Plasticity-led evolution
	Empirically evaluating plasticity-led evolution
	Plasticity-led evolution in spadefoot toads
	Plasticity and macroevolution
	Conclusions
	References
17 Niche construction and the transition to herbivory: Phenotype switching and the organization of new nutritional modes
	Introduction
	How the bovine got its stomach
		Developmental symbiosis: the microbial-dependent development of the ruminant stomach
		Nutritional symbiosis: the microbe-dependent digestion of plant fiber
		Protective Symbiosis: the microbe-dependent detoxification of plant defense chemicals
	Perturbational and mediational niche construction
		Perturbational niche construction
		Mediational niche construction
	Niche construction, plasticity, and developmental scaffolding
	Implications for holobiont individuality
	Conclusion
	References
18 Nature, nurture, and noise in bird song ontogeny as determinants of phenotypic and functional variation among dialects
	Introduction: Song function, ontogeny, and phenotypic variation
		Functions of song
		Song ontogeny
		Patterns of phenotypic variation
	How phenotypic variation arises: plasticity in song development
		Extent of plasticity
		External influences
		Internal influences
		Stochasticity
		Results of plasticity
	Song dialects as functional polymorphisms
		How do dialects arise?
		Dialects and gene flow
		Functional variation among dialects
	Conclusion
	References
19 Domestication as a process generating phenotypic diversity
	Domestication in evolutionary terms
	Traditional view on possible mechanisms arisen of phenotypic diversity
	New insights into the nature of changes under domestication
		Farm-fox experiment
	Phenotypic changes of experimental foxes
	Constraints of development and its focus
	Phenotypic changes of domesticated foxes and developmental rate
	Acknowledgment
	References
	Further reading
20 The glycobiology of ovarian cancer progression: phenotypic switches and microenvironmental influences
	Introduction
	Glycobiology and cancer
	Ovarian cancer progression
		How it begins
		How it transitions
		How it colonizes
	N- and O-linked glycoproteins
	Proteoglycans in ovarian cancer
	Lectins
	Cancer evolution and glycan-driven plasticity
	Conclusion
	Acknowledgments
	References
21 Epithelial-mesenchymal transition in cancer
	Introduction
	Epithelial-mesenchymal transition
	Regulation of epithelial-mesenchymal transition
	Hybrid epithelial/mesenchymal phenotypes
	Therapeutic strategies targeting epithelial-mesenchymal plasticity
	Acknowledgments
	References
22 Phenotypic switching and prostate diseases: a model proposing a causal link between benign prostatic hyperplasia and pro...
	Introduction
	From BPH to PCa via EMT/MET
	The Integrated Model
	The key drivers of EMT/MET in PCa are IDPs
	Phenotypic plasticity is a manifestation of plasticity at the molecular level
	Conclusions and future directions
	References
23 Phenotypic plasticity and lineage switching in prostate cancer
	Prostate development and the progression to prostate cancer
	Targeting the androgen receptor signaling axis in prostate adenocarcinoma
	Treatment-induced phenotypic plasticity overcomes androgen receptor blockade
		Overcoming resource depletion
		Plasticity-driven metastasis
		Epithelial plasticity in immune evasion
	EMT and NEPC—common molecular drivers with unique phenotypic outputs?
	Phenotypic plasticity is a dynamic driver of prostate cancer aggression
	References
24 Implications of non-genetic heterogeneity in cancer drug resistance and malignant progression
	Introduction
		Theory of cell states in a phenotypic landscape
	Experimental evidence for nongenetic heterogeneity
		Well-characterized cell states: epithelial-to-mesenchymal transition
		Observations of drug naïve cell states
		Adaptive cell states that are induced in response to cancer treatment
	Future of cell state characterization: defining cell states via relevant heterogeneity
	References
25 Phenotypic plasticity: the emergence of cancer stem cells and collective cell migration
	Phenotypic plasticity and cancer stem cells
	The landscape of epithelial-mesenchymal plasticity
	Senescence and cancer cell plasticity
	Phenotypic transformations and collective cell migration
	Concluding remarks
	References
26 Adaptive phenotypic switching in breast cancer in response to matrix deprivation
	Heterogeneity and phenotypic plasticity in cancer
	Sensing matrix deprivation
	Signaling pathways regulating metabolic plasticity
		The PI3K/Akt-mTOR pathway
		AMPK pathway
	Role of metabolic plasticity in cancer cell survival under matrix deprivation
		Plasticity in glucose metabolism
		Plasticity in redox signaling
		Plasticity in lipid metabolism
		Plasticity in amino acid metabolism
		Role of autophagy in the adaptive phenotypic switch
	Bistable systems and plasticity
		AMPK-Akt double negative feedback loop confers bistability to the metabolic phenotype
	Matrix deprivation and EMT
	Matrix deprivation and stemness
		Matrix deprivation expands the limited plasticity of normal mammary epithelium
		Matrix deprivation enhances stemness properties in cancer cells
	EMT and stemness are associated with metabolic reprogramming in cancer
	Future directions
	References
27 Phenotypic instability induced by tissue disruption at the origin of cancer
	Introduction
	Phenotypic plasticity in cancer growth and drug resistance: role of cancer stem cells and stochastic gene expression
	Cellular plasticity and stemness conferred by high stochastic gene expression
	Cell–cell interactions as constraints decreasing cellular plasticity and stemness during differentiation
	Tissue disruption at the origin of phenotypic instability and consequently cancer
	References
28 Evolutionary strategies to overcome cancer cell resistance to treatment
	Introduction
		Evolution in cancer
		Evolution, phenotypic switching, and cancer therapy
		Can evolution be integrated into cancer therapy?
		Evolution during cancer therapy
		Incorporating evolutionary principles into cancer treatment
		Adaptive therapy
		Can the cost of resistance be increased?
		Double bind
	Conclusion
	References
Index