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A discussion of some of the challenges and promise of single-cell technology.

The Human Breast Cell Atlas identifies 12 major breast cell types and 58 biological cell states, revealing abundant pericyte, endothelial and immune cell populations, and highly diverse luminal epithelial cell states.

Retromer complex cooperates with Vps5 and Vps17 in yeast to traffic transmembrane proteins. Here, the authors present structural and functional studies that reveal the mechanism of Retromer and Vps5 interaction.

Nicholas Navin and colleagues use highly multiplexed single-nucleus sequencing to investigate DNA copy number evolution in patients with triple-negative breast cancer. Their data suggest that most copy number alterations are acquired at the earliest stages of tumor evolution in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.

In the final report of a phase 1 trial evaluating intracerebroventricular B7-H3-targeting CAR T cells in children and young adults with diffuse intrinsic pontine glioma, repeated intracranial infusions were feasible and well tolerated with a median overall survival of 19.8 months and 3 patients surviving over 40 months from diagnosis.

Cooperative interactions among tumor cells may have important implications for metastasis. Here, the authors examined the spatio-temporal nature of interactions among clonal populations of ovarian carcinoma cells and found that transient interactions cells can promote metastases via commensal interactions.

Using single-cell DNA sequencing we show that most healthy women harbour rare populations of aneuploid epithelial cells with copy number alteration events in their breast tissue that expand and accumulate with age.

Monopogen identifies single-nucleotide variants in single-cell sequencing data.

A new statistical approach mitigates technical errors in single-cell DNA sequencing data to advance the study of tumor evolution and diversity.

CellTrek maps single cells to their spatial coordinates in tissues.

In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.

Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.

Clonal subpopulations in human tumors are identified from single-cell RNA-seq data.

The authors use lineage tracing to map the fate of wild-type and Brca1^−/−;Trp53^−/− cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization.

Gulhati et al. demonstrate therapeutic efficacy for combinatorial administration of 41BB agonist, LAG3 antagonist and a CXCR1/2 inhibitor in murine pancreatic cancer models, resulting in a remodeled tumor microenvironment.

A genomic analysis of ductal carcinoma in situ (DCIS) samples with matched ipsilateral invasive breast cancer recurring later shows that around 18% of tumors were unrelated to the DCIS, and had distinct clonal origins.

Single-cell DNA methylation and transcriptomic glioma analyses link local DNA methylation disorder and cellular plasticity. Increases in disorder are associated with stress and disease progression, suggesting a role in shaping the therapeutic response.

Single-cell analysis of genomes from primary human breast tumours and cell lines shows that chromosomal aberrations continue to evolve during primary tumour expansion, resulting in a milieu of subclones within the tumour.

Mutations in TP53 gene are very common in cancer development. Here the authors take advantage of murine models to show that somatic Trp53 mutations differentially drive breast cancer and evolution of metastases.

Immunotherapies now dominate the treatment landscape for melanoma, but why they only work in a subset of patients remains unclear. Here, the authors perform an immunogenomic analysis on 67 intratumor sub-regions of a PD-1 inhibitor resistant melanoma, and 2 additional metastases from a single patient, mapping the spatial relationships between genomic and immune heterogeneity at high resolution.

Monoclonal antibody (mAb) therapy is now commonplace in the clinic, yet such reagents can elicit unwanted side effects due to interactions with Fcγ receptors. Georgiou and colleagues have engineered mAbs that lack such FcγR interactions but retain the ability to activate complement and show that these modified mAbs have efficacious effector function.

To investigate genomic diversity within tumours, a new type of whole-genome and exome single cell sequencing has been developed using G2/M nuclei; the technique was used to sequence single nuclei from an oestrogen-positive breast cancer and a triple-negative ductal carcinoma—aneuploidy rearrangements emerged as early events in tumour formation and then point mutations evolved gradually over time.

This Review discusses the role of functional (impacting tumour phenotype) and non-functional intra-tumour heterogeneity (ITH) in cancer evolution, highlighting the importance of considering genetic and non-genetic factors and their impact on patient outcomes.

Oncogenic driver mutations are identified in single cells by a transposon-based sequencing method.

Single cell RNA sequencing is a powerful tool for understanding cellular diversity but is limited by cost, throughput and sample preparation. Here the authors use nanogrid technology with integrated imaging to sequence thousands of cancer nuclei in parallel from fresh or frozen tissue.

Although it is known that tumours are genetically heterogeneous it has so far been difficult to dissect this heterogeneity at a single cell level. This paper combines whole-genome amplification and next-generation sequencing of flow-sorted nuclei from breast tumours to investigate their population structure and evolution. In contrast to gradual models of tumour progression, the results indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.

‘Ductal carcinoma in situ’ (DCIS) describes abnormal cells in the milk ducts. DCIS is often non-invasive, although a small proportion of cases leave the ducts and progress to invasive breast cancer. This Review discusses the existing data for distinguishing progressive and non-progressive DCIS, with a focus on informing current disease management strategies.

In this Perspective, attendees of the Herrenhausen Tumour Heterogeneity meeting discuss the challenges in understanding tumour heterogeneity and propose ways forward for overcoming these hurdles.

Monovar efficiently detects single-nucleotide variants in single-cell DNA sequence data with high sensitivity and specificity.

This single nucleus-targeted sequencing approach incorporates multiplexing and targeted capture for efficient high-throughput detection of genome variants. The protocol will be particularly useful for studying rare cells and complex cell populations.

The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and for other microscopy data to highly multiplexed tissue images and traditional histology.