RESUMO
The development of multiomic profiling tools has rapidly expanded in recent years, along with their use in profiling skin tissues in various contexts, including dermatologic diseases. Among these tools, single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) have emerged as widely adopted and powerful assays for elucidating key cellular components and their spatial arrangement within skin disease. In this paper, we review the recent biological insights gained from the use of scRNA-seq and ST and the advantages of combining both for profiling skin diseases, including aberrant wound healing, inflammatory skin diseases, and cancer. We discuss the role of scRNA-seq and ST in improving skin disease treatments and moving toward the goal of achieving precision medicine in dermatology, whereby patients can be optimally matched to treatments that maximize therapeutic response.
RESUMO
Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.