bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022‒08‒21
two papers selected by
Sergio Marchini
Humanitas Research

  1. Cancer Res. 2022 Aug 15. pii: CAN-21-3819. [Epub ahead of print]
      High-grade serous cancer (HGSC) is the most common subtype of ovarian cancer. HGSC is highly aggressive with poor patient outcomes, and a deeper understanding of HGSC tumorigenesis could help guide future treatment development. To systematically characterize the underlying pathological mechanisms and intratumoral heterogeneity in human HGSC, we used an optimized single-cell multiomics sequencing technology to simultaneously analyze somatic copy number alterations (SCNA), DNA methylation, chromatin accessibility, and transcription in individual cancer cells. Genes associated with interferon (IFN) signaling, metallothioneins, and metabolism were commonly upregulated in ovarian cancer cells. Integrated multiomics analyses revealed that upregulation of IFN signaling and metallothioneins was influenced by both demethylation of their promoters and hypomethylation of satellites and LINE1, and potential key transcription factors regulating glycolysis using chromatin accessibility data were uncovered. Additionally, gene expression and DNA methylation displayed similar patterns in matched primary and metastatic tumor cells of the same genetic lineage, suggesting that metastatic cells potentially preexist in subclones of primary tumors. Finally, the lineages of cancer cells with higher residual DNA methylation levels and upregulated expression of CCN1 and HSP90AA1 presented greater metastatic potential. This study characterizes the critical genetic, epigenetic, and transcriptomic features and their mutual regulatory relationships in ovarian cancer, providing valuable resources for identifying new molecular mechanisms and potential therapeutic targets for HGSC.
  2. Nature. 2022 Aug 17.
      Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2-5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6 and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.