Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.

Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis , compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.

Emergence of allostery through reorganization of protein residue network architecture.

Despite more than a century of study, consensus on the molecular basis of allostery remains elusive. A comparison of allosteric and non-allosteric members of a protein family can shed light on this important regulatory mechanism, and the bacterial biotin protein ligases, which catalyze post-translational biotin addition, provide an ideal system for such comparison. While the Class I bacterial ligases only function as enzymes, the bifunctional Class II ligases use the same structural architecture for an additional transcription repression function. This additional function depends on allosterically activated homodimerization followed by DNA binding. In this work, we used experimental, computational network, and bioinformatics analyses to uncover distinguishing features that enable allostery in the Class II biotin protein ligases. Experimental studies of the Class II Escherichia coli protein indicate that catalytic site residues are critical for both catalysis and allostery. However, allostery also depends on amino acids that are more broadly distributed throughout the protein structure. Energy-based community network analysis of representative Class I and Class II proteins reveals distinct residue community architectures, interactions among the communities, and responses of the network to allosteric effector binding. Bioinformatics mutual information analyses of multiple sequence alignments indicate distinct networks of coevolving residues in the two protein families. The results support the role of divergent local residue community network structures both inside and outside of the conserved enzyme active site combined with distinct inter-community interactions as keys to the emergence of allostery in the Class II biotin protein ligases.