The architecture of an organ is built through interactions between its native cells and its connective tissue consisting of stromal cells and the extracellular matrix (ECM). Upon transformation through tumorigenesis, such interactions are disrupted and replaced by a new set of intercommunications between malignantly transformed parenchyma, an altered stromal cell population, and a remodeled ECM. In this perspective, we propose that the intratumoral heterogeneity of cancer cell phenotypes is an emergent property of such reciprocal intercommunications, both biochemical and mechanical-physical, which engender and amplify the diversity of cell behavioral traits. An attempt to assimilate such findings within a framework of phenotypic plasticity furthers our understanding of cancer progression.

Several post-translational protein modifications lie predominantly within regions of disorder: the biased localization has been proposed to expand the binding versatility of disordered regions. However, investigating a representative dataset of 500 human N-glycoproteins, we observed the sites of n-linked glycosylations or n-glycosites, to be predominantly present in the regions of predicted order. When compared with disordered stretches, ordered regions were not found to be enriched for asparagines, serines and threonines, residues that constitute the sequon signature for conjugation of N-glycans. We then investigated the basis of mutual exclusivity between disorder and N-glycosites on the basis of amino acid distribution: when compared with control ordered residue stretches without any N-glycosites, residue neighborhoods surrounding N-glycosites showed a depletion of bulky, hydrophobic and disorder-promoting amino acids and an enrichment for flexible and accessible residues that are frequently found in coiled structures. When compared with control disordered residue stretches without any N-glycosites, N-glycosite neighborhoods were depleted of charged, polar, hydrophobic and flexible residues and enriched for aromatic, accessible and order-promoting residues with a tendency to be part of coiled and β structures. N-glycosite neighborhoods also showed greater phylogenetic conservation among amniotes, compared with control ordered regions, which in turn were more conserved than disordered control regions. our results lead us to propose that unique primary structural compositions and differential propensities for evolvability allowed for the mutual spatial exclusion of n-glycosite neighborhoods and disordered stretches.One of the common co-and post-translational modifications of polypeptides is the conjugation of branched glycosylations to asparagines (known as N-linked glycosylations) 1 . N-linked glycosylation begins with the assembly of an oligosaccharide on dolichol pyrophosphate and the subsequent transfer of the oligosaccharide to the asparagine residues of polypeptides in the lumen of the endoplasmic reticulum; the oligosaccharide is further remodeled in the Golgi complex. Several proteins that end up in the extracellular milieu or as transmembrane proteins are N-linked glycoconjugates. The establishment of organismal morphologies has been sought to be understood through the interactions of a highly conserved set of proteins known as the developmental genetic toolkit 2 . Most toolkit proteins, which are involved in tissue-scale processes, such as cell-cell and cell-matrix adhesion, diffusion-driven signaling and cell movement, are extracellular-or membrane-bound glycoproteins 3,4 . The fundamental role of such toolkit proteins in mechanisms of organ-and organismal-development across diverse clades suggests evolutionary constraints on their structures and folds, while they may have continued to evolve to perform newer functions as organisms occupied and constructed newer niches.A large number of eukaryotic pro...

6Several post-translational modifications of proteins lie within regions of disorder, stretches of 7 amino acid residues that exhibit a dynamic tertiary structure and resist crystallization. Such 8 localization has been proposed to expand the binding versatility of the disordered regions, and 9 hence, the repertoire of interacting partners for the proteins. However, investigating a dataset of 1 0 500 human N-linked glycoproteins, we observed that the sites of N-linked glycosylations, or N-1 1 glycosites, lay predominantly within the regions of predicted order rather than their unstructured 1 2 counterparts. This mutual exclusivity between disordered stretches and N-glycosites could not be 1 3 reconciled merely through asymmetry in distribution of asparagines, serines or threonines 1 4 residues, which comprise the minimum-required signature for conjugation by N-linked glycans, 1 5but rather by a contextual enrichment of these residues next to each other within the ordered 1 6 portions. In fact, N-glycosite neighborhoods and disordered stretches showed distinct sets of 1 7 enriched residues suggesting their individualized roles in protein phenotype. N-glycosite 1 8 neighborhood residues also showed higher phylogenetic conservation than disordered stretches 1 9

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