Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite-Protein Physical Interaction Subnetworks Altered in Cancer.

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.

Imaging the future: the emerging era of single-cell spatial proteomics.

The proteome of a human cell is partitioned within organelles, such as the nucleus, and other subcellular compartments, such as the cytoplasm, forming a myriad of membrane-bound and membrane-free ultrastructures. This compartmentalization allows discrete biochemical processes to occur efficiently in isolation, with relevant proteins localized to appropriate niches to fulfill their biological function(s). Proper delivery and dynamic exchange of proteins between compartments underlie the regulation of many cellular processes, such as cell signaling, division, and programmed cell death. To this end, cells deploy dedicated trafficking mechanisms to ensure correct protein localization, as mis-localization can result in pathology. In addition to trafficking, variation in the expression, modification, and physical associations of proteins within and between cells can result in biological heterogeneity, motivating the need for single-cell measurements. In this review, we introduce diverse platform technologies developed for subcellular proteomics and high-throughput systems biology, with the aim of providing mechanistic insights into fundamental cell biological processes underlying healthy and diseased states, and valuable public data resources. In contrast to the rapidly advancing field of single-cell genomics, the single-cell spatial proteomics toolbox remains in its infancy, but is poised to make considerable advances in the coming years.

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.

G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.