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• W3020142913 abstract "Proliferation pathways are determined by the genome sequence, 3D organization and chromatin accessibility, and influenced by protein availability prior to cancer emergence.Parallel proliferation pathways lead to the same function, albeit through different routes.Parallel proliferation pathways can lead to cell robustness as in the case of drug resistance; however, the emergence of cancer signaling pathways is context-dependent, associated with organ-specific cell lineage and the microenvironment.Proliferation pathways are cell type and state specific.If the pathways populating the same cell type involve the same proteins (nodes), or proteins of the same families they are ‘redundant’; if different, they are ‘parallel’; the smaller chromatin alteration suggests that redundant pathways are more pervasive. Are the receptor tyrosine kinase (RTK) and JAK-STAT-driven proliferation pathways ‘parallel’ or ‘redundant’? And what about those of K-Ras4B versus N-Ras? ‘Parallel’ proliferation pathways accomplish a similar drug resistance outcome. Thus, are they ‘redundant’? In this paper, it is argued that there is a fundamental distinction between ‘parallel’ and ‘redundant’. Cellular proliferation pathways are influenced by the genome sequence, 3D organization and chromatin accessibility, and determined by protein availability prior to cancer emergence. In the opinion presented, if they operate the same downstream protein families, they are redundant; if evolutionary-independent, they are parallel. Thus, RTK and JAK-STAT-driven proliferation pathways are parallel; those of Ras isoforms are redundant. Our Precision Medicine Call to map cancer proliferation pathways is vastly important since it can expedite effective therapeutics. Are the receptor tyrosine kinase (RTK) and JAK-STAT-driven proliferation pathways ‘parallel’ or ‘redundant’? And what about those of K-Ras4B versus N-Ras? ‘Parallel’ proliferation pathways accomplish a similar drug resistance outcome. Thus, are they ‘redundant’? In this paper, it is argued that there is a fundamental distinction between ‘parallel’ and ‘redundant’. Cellular proliferation pathways are influenced by the genome sequence, 3D organization and chromatin accessibility, and determined by protein availability prior to cancer emergence. In the opinion presented, if they operate the same downstream protein families, they are redundant; if evolutionary-independent, they are parallel. Thus, RTK and JAK-STAT-driven proliferation pathways are parallel; those of Ras isoforms are redundant. Our Precision Medicine Call to map cancer proliferation pathways is vastly important since it can expedite effective therapeutics. Proliferation is essential for tumor development, and in cancer cells, proliferation pathways emerge from both redundant and parallel signaling pathways. ‘Redundant’ signaling pathways are defined here as those which occur in the same protein family, such as K-Ras, H-Ras, and N-Ras, downstream effectors of receptor tyrosine kinase (RTK) pathways (Box 1), to achieve the same outcome (i.e., cellular proliferation). ‘Parallel’ signaling pathways are defined here as those which are functionally and evolutionary distinct, such as Wnt, Notch, Hedgehog, and Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) pathways, but also capable of promoting cellular proliferation and survival upon activation.Box 1Ras Isoforms as Examples for Redundant Proliferation PathwaysRedundant pathways can be exemplified by H-Ras, K-Ras, and N-Ras isoforms that originated from a single gene (or gene family), but acquired modified C-terminal tails with altered charge, hydrophobicity, and inclusion of sequence signatures that are differentially post-translationally modified. These modifications tailor them to certain membrane properties, and cell-specific activation and signaling scenarios [82.Nussinov R. et al.Oncogenic ras isoforms signaling specificity at the membrane.Cancer Res. 2018; 78: 593-602Crossref PubMed Scopus (68) Google Scholar]. Early on, the high similarity of the sequences and structures of their catalytic domains led to the hypothesis that Ras isoforms are physiologically and pathologically redundant, and that consequently observations made on H-Ras (which has been easier to clone, express, and crystallize) apply to all isoforms, a hypothesis later shown flawed, as H-Ras, K-Ras, and N-Ras isoforms have specific context-dependent functions [46.Hobbs G.A. et al.RAS isoforms and mutations in cancer at a glance.J. Cell Sci. 2016; 129: 1287-1292Crossref PubMed Scopus (483) Google Scholar,82.Nussinov R. et al.Oncogenic ras isoforms signaling specificity at the membrane.Cancer Res. 2018; 78: 593-602Crossref PubMed Scopus (68) Google Scholar], as do isoforms of other proteins (e.g., [7.Tusa I. et al.ERK5 is activated by oncogenic BRAF and promotes melanoma growth.Oncogene. 2018; 37: 2601-2614Crossref PubMed Scopus (37) Google Scholar,83.Thorpe L.M. et al.PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.Nat. Rev. Cancer. 2015; 15: 7-24Crossref PubMed Scopus (883) Google Scholar, 84.Zhang M. et al.The mechanism of PI3Kalpha activation at the atomic level.Chem. Sci. 2019; 10: 3671-3680Crossref PubMed Google Scholar, 85.Hu J. et al.Allosteric activation of functionally asymmetric RAF kinase dimers.Cell. 2013; 154: 1036-1046Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 86.Terrell E.M. et al.Distinct binding preferences between Ras and Raf family members and the impact on oncogenic Ras signaling.Mol. Cell. 2019; 76: 872-884.e5Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 87.Stefanini L. et al.Functional redundancy between RAP1 isoforms in murine platelet production and function.Blood. 2018; 132: 1951-1962Crossref PubMed Scopus (28) Google Scholar, 88.Hedman A.C. et al.The biology of IQGAP proteins: beyond the cytoskeleton.EMBO Rep. 2015; 16: 427-446Crossref PubMed Scopus (138) Google Scholar]). They also have different mutational spectrum and therapeutic outcomes [46.Hobbs G.A. et al.RAS isoforms and mutations in cancer at a glance.J. Cell Sci. 2016; 129: 1287-1292Crossref PubMed Scopus (483) Google Scholar,47.Prior I.A. et al.A comprehensive survey of Ras mutations in cancer.Cancer Res. 2012; 72: 2457-2467Crossref PubMed Scopus (1246) Google Scholar]. They are preferentially expressed in specialized cell types due to their pre-existing cell-specific chromatin accessibility status and environment. For example, signaling in a colon cell, where K-Ras is populated, differs from that of skin cell, where N-Ras is, although still accomplishing similar functions. However, even though their protein-protein interaction networks differ [89.Brubaker D.K. et al.Proteogenomic network analysis of context-specific KRAS signaling in mouse-to-human cross-species translation.Cell Syst. 2019; 9: 258-270.e6Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar], a relatively small chromatin alteration emerging in drug resistance can hijack a Ras isoform pathway by making it accessible. Drug resistance to any targeted mutant Ras isoform can result in activation of a redundant pathway involving another isoform accomplishing the same function (i.e., cell proliferation). Redundant pathways can be exemplified by H-Ras, K-Ras, and N-Ras isoforms that originated from a single gene (or gene family), but acquired modified C-terminal tails with altered charge, hydrophobicity, and inclusion of sequence signatures that are differentially post-translationally modified. These modifications tailor them to certain membrane properties, and cell-specific activation and signaling scenarios [82.Nussinov R. et al.Oncogenic ras isoforms signaling specificity at the membrane.Cancer Res. 2018; 78: 593-602Crossref PubMed Scopus (68) Google Scholar]. Early on, the high similarity of the sequences and structures of their catalytic domains led to the hypothesis that Ras isoforms are physiologically and pathologically redundant, and that consequently observations made on H-Ras (which has been easier to clone, express, and crystallize) apply to all isoforms, a hypothesis later shown flawed, as H-Ras, K-Ras, and N-Ras isoforms have specific context-dependent functions [46.Hobbs G.A. et al.RAS isoforms and mutations in cancer at a glance.J. Cell Sci. 2016; 129: 1287-1292Crossref PubMed Scopus (483) Google Scholar,82.Nussinov R. et al.Oncogenic ras isoforms signaling specificity at the membrane.Cancer Res. 2018; 78: 593-602Crossref PubMed Scopus (68) Google Scholar], as do isoforms of other proteins (e.g., [7.Tusa I. et al.ERK5 is activated by oncogenic BRAF and promotes melanoma growth.Oncogene. 2018; 37: 2601-2614Crossref PubMed Scopus (37) Google Scholar,83.Thorpe L.M. et al.PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.Nat. Rev. Cancer. 2015; 15: 7-24Crossref PubMed Scopus (883) Google Scholar, 84.Zhang M. et al.The mechanism of PI3Kalpha activation at the atomic level.Chem. Sci. 2019; 10: 3671-3680Crossref PubMed Google Scholar, 85.Hu J. et al.Allosteric activation of functionally asymmetric RAF kinase dimers.Cell. 2013; 154: 1036-1046Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 86.Terrell E.M. et al.Distinct binding preferences between Ras and Raf family members and the impact on oncogenic Ras signaling.Mol. Cell. 2019; 76: 872-884.e5Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 87.Stefanini L. et al.Functional redundancy between RAP1 isoforms in murine platelet production and function.Blood. 2018; 132: 1951-1962Crossref PubMed Scopus (28) Google Scholar, 88.Hedman A.C. et al.The biology of IQGAP proteins: beyond the cytoskeleton.EMBO Rep. 2015; 16: 427-446Crossref PubMed Scopus (138) Google Scholar]). They also have different mutational spectrum and therapeutic outcomes [46.Hobbs G.A. et al.RAS isoforms and mutations in cancer at a glance.J. Cell Sci. 2016; 129: 1287-1292Crossref PubMed Scopus (483) Google Scholar,47.Prior I.A. et al.A comprehensive survey of Ras mutations in cancer.Cancer Res. 2012; 72: 2457-2467Crossref PubMed Scopus (1246) Google Scholar]. They are preferentially expressed in specialized cell types due to their pre-existing cell-specific chromatin accessibility status and environment. For example, signaling in a colon cell, where K-Ras is populated, differs from that of skin cell, where N-Ras is, although still accomplishing similar functions. However, even though their protein-protein interaction networks differ [89.Brubaker D.K. et al.Proteogenomic network analysis of context-specific KRAS signaling in mouse-to-human cross-species translation.Cell Syst. 2019; 9: 258-270.e6Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar], a relatively small chromatin alteration emerging in drug resistance can hijack a Ras isoform pathway by making it accessible. Drug resistance to any targeted mutant Ras isoform can result in activation of a redundant pathway involving another isoform accomplishing the same function (i.e., cell proliferation). Redundant signaling pathways can emerge during development, via gene duplication and modification [1.Kitano H. Biological robustness.Nat. Rev. Genet. 2004; 5: 826-837Crossref PubMed Scopus (1746) Google Scholar, 2.Conant G.C. Wagner A. Convergent evolution of gene circuits.Nat. Genet. 2003; 34: 264-266Crossref PubMed Scopus (148) Google Scholar, 3.Teichmann S.A. Babu M.M. Gene regulatory network growth by duplication.Nat. Genet. 2004; 36: 492-496Crossref PubMed Scopus (403) Google Scholar, 4.D’Antonio M. Ciccarelli F.D. Modification of gene duplicability during the evolution of protein interaction network.PLoS Comput. Biol. 2011; 7e1002029Crossref PubMed Scopus (39) Google Scholar]. Their emergence is essential since embryonic or cell-type specific pathways may become inaccessible in the densely packed chromatin of specialized cells, and a related pathway can be activated in response to the drug treatment of another, resulting in drug resistance and cell robustness [5.Lavi O. Redundancy: a critical obstacle to improving cancer therapy.Cancer Res. 2015; 75: 808-812Crossref PubMed Scopus (39) Google Scholar]. By contrast, parallel proliferation pathways can, as indicated earlier, emerge from signaling pathways that accomplish distinct functions in cellular development, but have proliferative capabilities that can also be inducted by the cancer cell; the emergence of cancer signaling pathways is context-dependent, associated with organ-specific cell lineage and the microenvironment [6.Sack L.M. et al.Profound tissue specificity in proliferation control underlies cancer drivers and aneuploidy patterns.Cell. 2018; 173: 499-514.e23Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. It should be noted that parallel proliferation pathways are often considered redundant because they can fulfil the role of cellular proliferation substituting for the original inhibited pathway. Many signaling pathways related to cancer development are known, but some still unknown and some only partially known. Even though, in principle, every cell can proliferate through all possible proliferation pathways, that is not the case in vivo. Under physiological conditions, it is likely that only one pathway is available in a given cell type and state, and others are suppressed. Pathway accessibility also implies availability of every downstream protein in the pathway. Therefore, when drugs block the pathway, resistance can emerge through activation of other redundant or parallel proliferation pathways (Figure 1). For example, cases of redundant pathways can be seen when inhibition of the epidermal growth factor receptor (EGFR) (lung cancer) results in activation of receptor tyrosine kinase erbB-2/3 (ERBB2/3) (breast cancer) (Figure 1), or when ERK5 substitutes for ERK1/2 after drug treatment [7.Tusa I. et al.ERK5 is activated by oncogenic BRAF and promotes melanoma growth.Oncogene. 2018; 37: 2601-2614Crossref PubMed Scopus (37) Google Scholar]. In these cases, signaling takes place through the same downstream protein families (i.e., Ras, Raf, MEK, and ERK) to promote cell proliferation. Redundant signaling pathways can also be exemplified by H-Ras, K-Ras, and N-Ras isoforms (Box 1). Alternatively, cancer cells can activate parallel pathways that execute distinct functions in organism development and act through evolutionary-independent proteins, as in the case of JAK-STAT pathways (Figure 1, right); this ultimately results in increased cell proliferation and survival. To envisage the formidable challenge of identifying all proliferation pathways, one should consider that in addition to mutations, even different ligands (as in the case of EGFR [8.Freed D.M. et al.EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics.Cell. 2017; 171: 683-695.e18Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]), and protein levels, etc., can elicit different pathways and outcomes. In addition to these aspects complicating the identification of redundant and parallel proliferation pathways, one must also consider the accessibility of the genome, as the genome encodes pathways which are required for organism development and sustained differentiated functions. Differential cell-specific gene expression (and degradation) emerges through dynamic chromatin states [9.Hansen A.S. et al.Recent evidence that TADs and chromatin loops are dynamic structures.Nucleus. 2018; 9: 20-32Crossref PubMed Scopus (122) Google Scholar, 10.Fierz B. Poirier M.G. Biophysics of chromatin dynamics.Annu. Rev. 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As a result of cell state (i.e., cell or tumor type-specificity or presence of drug treatment), paltry signaling pathways can become populated, and enriched ones may become sparse (e.g., in the Figure 1 example of EGFR mutation activating ERB2/ERB3). As discussed later, there is a staggering challenge to unravel how genome accessibility and resulting protein networks of cell- or tumor-specific lineages explain isoform distributions in specific cancers, as well as their mutational spectra [14.Haigis K.M. et al.Tissue-specificity in cancer: the rule, not the exception.Science. 2019; 363: 1150-1151Crossref PubMed Scopus (83) Google Scholar]. These challenges merge with the computationally highly intensive challenge to identify all (frequent, rare, and latent [15.Nussinov R. Tsai C.J. ‘Latent drivers’ expand the cancer mutational landscape.Curr. Opin. Struct. Biol. 2015; 32: 25-32Crossref PubMed Scopus (55) Google Scholar]) activating mutations in each downstream protein in each pathway. Ultimately, the challenges are in figuring out: (i) how many redundant and parallel signaling pathways exist for proliferation, (ii) which are they, and (iii) which are their activating mutations. Here, the focus is on identification of cell-specific proliferation pathways. Beginning with the introduction of the free energy landscape (see Glossary) of chromatin to describe genome accessibility. Then the provision of numerous examples of tissue- and cancer-specific proliferation pathways, before linking them back to genome accessibility. Finally, the provision of further discussion on proliferation pathways and genome accessibility. The theory presented here is that a complete list of proliferation pathways, coupled with cancer genome resources and a patient’s data, can identify the candidate drug resistant pathways to target. Merging the candidate list with cell-specific chromatin accessibility data on genome organization computed based on the energy landscape theory can validate the identification. How can one assess genome accessibility of resulting protein networks within a candidate list of cell-specific proliferation pathways? The concept of the free energy landscape and the statistical description of the states populating it have transformed the field of protein folding [16.Bryngelson J.D. et al.Funnels, pathways, and the energy landscape of protein folding: a synthesis.Proteins. 1995; 21: 167-195Crossref PubMed Scopus (2285) Google Scholar], but the genome size and organization vastly compound the problem [17.Zhang B. Wolynes P.G. Genomic energy landscapes.Biophys. J. 2017; 112: 427-433Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. How the free energy landscape concept can be applied to genome organization is explored here. Proteins exist in stable folded conformations or in disordered ensembles lacking highly populated states but still near thermodynamic equilibrium. Their landscape describes the populated free energy basins and the kinetics of transitioning the barriers between them [18.Hegler J.A. et al.The spectrum of biomolecular states and motions.HFSP J. 2008; 2: 307-313Crossref PubMed Scopus (31) Google Scholar,19.Weinkam P. et al.Electrostatic effects on funneled landscapes and structural diversity in denatured protein ensembles.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 1796-1801Crossref PubMed Scopus (52) Google Scholar]. Since the distribution of their states control their actions, their statistical description links folding with function [20.Nussinov R. et al.Protein ensembles link genotype to phenotype.PLoS Comput. Biol. 2019; 15e1006648Crossref PubMed Scopus (31) Google Scholar]. A landscape view is powerful since it can explain how the cellular environment can activate (or repress) protein activity through a shift of the populations [21.Ma B. et al.Folding funnels and binding mechanisms.Protein Eng. 1999; 12: 713-720Crossref PubMed Scopus (485) Google Scholar]; such a dynamic description of proteins is the basis of allostery [22.Nussinov R. Tsai C.J. Allostery in disease and in drug discovery.Cell. 2013; 153: 293-305Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar,23.Tsai C.J. Nussinov R. A unified view of “how allostery works”.PLoS Comput. Biol. 2014; 10e1003394Crossref PubMed Scopus (269) Google Scholar]. The energy landscape adopts concepts from the theory of phase and glass transitions; however, it considers them within the framework of a system of finite size [17.Zhang B. Wolynes P.G. Genomic energy landscapes.Biophys. J. 2017; 112: 427-433Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. This raises the question of whether the landscape theory can be applied to the genome. Proteins undergo thermal motion on the timescale of nanoseconds, while large-scale changes can extend over hours. Considering size and complexity, genome dynamics is commonly believed to stretch over timescales of nanoseconds to hours, making quantitative modeling and linkage to function challenging (for discussion of timescales see [10.Fierz B. Poirier M.G. Biophysics of chromatin dynamics.Annu. Rev. Biophys. 2019; 48: 321-345Crossref PubMed Scopus (60) Google Scholar,24.Hubner M.R. Spector D.L. Chromatin dynamics.Annu. Rev. Biophys. 2010; 39: 471-489Crossref PubMed Scopus (119) Google Scholar]). Thus, different from proteins, the global structure of the genome is inherently an ensemble and not a funnel shape [25.Cremer T. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar]. High resolution experimental structures are lacking, and the size and complexity argue that genome populations are kinetically trapped, pointing to a system which is not at equilibrium. Despite these hurdles, the energy landscape theory was applied to chromosomes [26.Di Pierro M. et al.Transferable model for chromosome architecture.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 12168-12173Crossref PubMed Scopus (163) Google Scholar,27.Qi Y. Zhang B. Predicting three-dimensional genome organization with chromatin states.PLoS Comput. Biol. 2019; 15e1007024Crossref PubMed Scopus (55) Google Scholar]. 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• W3020142913 created "2020-05-01" @default.
• W3020142913 creator A5020262392 @default.
• W3020142913 creator A5025357844 @default.
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• W3020142913 date "2020-07-01" @default.
• W3020142913 modified "2023-10-06" @default.
• W3020142913 title "Are Parallel Proliferation Pathways Redundant?" @default.
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• W3020142913 doi "https://doi.org/10.1016/j.tibs.2020.03.013" @default.
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