Whole-cell energy modeling reveals quantitative changes of predicted energy flows in RAS mutant cancer cell lines.

Cellular utilization of available energy flows to drive a multitude of forms of cellular "work" is a major biological constraint. Cells steer metabolism to address changing phenotypic states but little is known as to how bioenergetics couples to the richness of processes in a cell as a whole. Here, we outline a whole-cell energy framework that is informed by proteomic analysis and an energetics-based gene ontology. We separate analysis of metabolic supply and the capacity to generate high-energy phosphates from a representation of demand that is built on the relative abundance of ATPases and GTPases that deliver cellular work. We employed mouse embryonic fibroblast cell lines that express wild-type KRAS or oncogenic mutations and with distinct phenotypes. We observe shifts between energy-requiring processes. Calibrating against Seahorse analysis, we have created a whole-cell energy budget with apparent predictive power, for instance in relation to protein synthesis.

Disease-Gene Networks of Skin Pigmentation Disorders and Reconstruction of Protein-Protein Interaction Networks.

Melanin, a light and free radical absorbing pigment, is produced in melanocyte cells that are found in skin, but also in hair follicles, eyes, the inner ear, heart, brain and other organs. Melanin synthesis is the result of a complex network of signaling and metabolic reactions. It therefore comes as no surprise that mutations in many of the genes involved are associated with various types of pigmentation diseases and phenotypes ('pigmentation genes'). Here, we used bioinformatics tools to first reconstruct gene-disease/phenotype associations for all pigmentation genes. Next, we reconstructed protein-protein interaction (PPI) networks centered around pigmentation gene products ('pigmentation proteins') and supplemented the PPI networks with protein expression information obtained by mass spectrometry in a panel of melanoma cell lines (both pigment producing and non-pigment producing cells). The analysis provides a systems network representation of all genes/ proteins centered around pigmentation and melanin biosynthesis pathways ('pigmentation network map'). Our work will enable the pigmentation research community to experimentally test new hypothesis arising from the pigmentation network map and to identify new targets for drug discovery.

Cell Adhesion Molecules in Normal Skin and Melanoma.

Cell adhesion molecules (CAMs) of the cadherin, integrin, immunoglobulin, and selectin protein families are indispensable for the formation and maintenance of multicellular tissues, especially epithelia. In the epidermis, they are involved in cell-cell contacts and in cellular interactions with the extracellular matrix (ECM), thereby contributing to the structural integrity and barrier formation of the skin. Bulk and single cell RNA sequencing data show that >170 CAMs are expressed in the healthy human skin, with high expression levels in melanocytes, keratinocytes, endothelial, and smooth muscle cells. Alterations in expression levels of CAMs are involved in melanoma propagation, interaction with the microenvironment, and metastasis. Recent mechanistic analyses together with protein and gene expression data provide a better picture of the role of CAMs in the context of skin physiology and melanoma. Here, we review progress in the field and discuss molecular mechanisms in light of gene expression profiles, including recent single cell RNA expression information. We highlight key adhesion molecules in melanoma, which can guide the identification of pathways and strategies for novel anti-melanoma therapies.