Cellular adaptation to cancer therapy along a resistance continuum.

Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance. In addition to genetic mutations, recent research has identified a role for non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework.

Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.

Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in >70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes associates with a strong reduction in desmosome gene expression.

Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment.

Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment.

Cancer cell states and emergent properties of the dynamic tumor system.

Phenotypic heterogeneity within malignant cells of a tumor is emerging as a key property of tumorigenesis. Recent work using single-cell transcriptomics has led to the identification of distinct cancer cell states across a range of cancer types, but their functional relevance and the advantage that they provide to the tumor as a system remain elusive. We present here a definition of cancer cell states in terms of coherently and differentially expressed gene modules and review the origins, dynamics, and impact of states on the tumor system as a whole.

Exploring tissue architecture using spatial transcriptomics.

Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for research in the life sciences. Recent technological advances in next-generation sequencing- and imaging-based approaches have established the power of spatial transcriptomics to measure expression levels of all or most genes systematically throughout tissue space, and have been adopted to generate biological insights in neuroscience, development and plant biology as well as to investigate a range of disease contexts, including cancer. Similar to datasets made possible by genomic sequencing and population health surveys, the large-scale atlases generated by this technology lend themselves to exploratory data analysis for hypothesis generation.

Author Correction: Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas.

A Correction to this paper has been published: https://doi.org/10.1038/s41587-019-0392-8.

Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates.

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population.

Plasticity and Clonality of Cancer Cell States.

While intratumoral heterogeneity has been extensively studied in terms of genetic alterations and phenotypic properties such as drug resistance, only recently has single-cell RNA-seq begun to expose the remarkable transcriptional diversity within tumors. A recent study of glioblastoma by Neftel et al. supports the emerging notion of cancer cell states and demonstrates their plasticity.