Extracellular matrix as a driver for intratumoral heterogeneity.

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.

Author Correction: Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins.

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 ß 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.