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In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment recommendations in 75% of cases.

The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.

Currently, there is limited understanding of the molecular subtypes of fumarate hydratase (FH)-deficient renal cell carcinoma (RCC). Here, the authors employ integrated genomics and transcriptomics to develop a CpG site-specific methylation signature for the identification of FH-deficient RCC, and to identify three distinct molecular subtypes for this rare but highly lethal kidney cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Personalized treatment for cancer patients relies on the deep characterization of tumor cells from patient biopsies. In this study, functional multi-omics profiling of a pan-cancer cohort of malignant serous effusions (MSE) finds strong coherence between MSE and matched solid tumors, underlining the feasibility and utility of multi-modal MSE-based precision oncology.

The diagnosis of prostate cancer brain metastasis (PCBM) has increased. Here, the authors investigate the landscape of somatic genetic alterations in brain metastases in a PCBM cohort of 51 patients with non-synchronous matched primary samples available for 20 patients.

Alimonti and colleagues show that coordinated activation of the Akt/mTOR and MNK/eIF4E pathways rewires the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells, which can be therapeutically targeted.

Multielement Z-tag X-ray fluorescence (MEZ-XRF) offers a new avenue for nondestructive and highly multiplexed tissue imaging and operates from the nanometer to whole-tissue scale, unlocking new biological observations.

Dormancy of disseminated cancer cells has been described in patients with breast cancer and associated with late metastatic relapses. Here the authors show that CD39⁺PD-1⁺CD8⁺ T cells correlate with increased disease free survival post-resection in breast cancer patients, and promote dormancy in a preclinical model.

The immunopathological features of SARS-CoV-2 infection in the lungs remain unclear. Here, the authors provide a comprehensive characterization of post mortem lung tissues of COVID-19 patients and find two distinct patterns characterized by differential expression of interferon stimulated genes (ISGs), which correlate to viral loads, cytokines, lung damage and time of hospitalization, suggesting ISG profiles to mark disease progression

A single-cell, spatially resolved analysis of breast cancer demonstrates the heterogeneity of tumour and stroma tissue and provides a more-detailed method of patient classification than the current histology-based system.

The detection of subclonal variants in heterogeneous cancer specimens is a challenge due to errors that occur during sequencing. In this study, a statistical algorithm and a sequencing strategy are reported that circumvent this issue and can accurately detect variants at a frequency as low as 1/10,000.

Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.

Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.

Long-read single-cell RNA sequencing is capable of detecting isoform-level gene expression and genomic alterations such as mutations and gene fusions, thereby providing cell-specific genotype-phenotype information. Here, the authors use long-read scRNA-seq on metastatic ovarian cancer samples and detect cell-type specific isoforms and gene fusions that may otherwise be misclassified in short-read data.

Paracrine signaling networks in the breast cancer microenvironment uncover determinants of hormone receptor status and offer opportunities for therapeutic intervention.

Different mutations found in endometrial and prostate tumors affecting the substrate-recognition ___domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al. and Dai et al., highlights the divergent effects of recurrent mutations affecting different residues within the same functional ___domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations.

Through combined deletion of Vhl, Trp53 and Rb1 in renal epithelial cells, the authors develop a new mouse model of renal cell carcinoma that recapitulates the cellular and molecular features of a large proportion of human tumors. This model uncovers a role for primary-cilium-related genes in the development of the disease and provides a reliable platform for preclinical therapeutic studies.

Lu and colleagues report that ASPP2 induces mesenchymal–epithelial transition and inhibits cancer cell invasion and metastasis by preventing the β-catenin-mediated upregulation of ZEB1.

Bodenmiller and colleagues present a method for three-dimensional analysis of tissue architecture using imaging mass cytometry and demonstrate the utility in resolving cellular interactions in the tumor microenvironment, in human breast cancer samples.

Shakhova, Sommer and colleagues use mouse models to demonstrate that the Sox10 transcription factor is crucial for the formation and maintenance of giant congenital naevi and melanoma. They show, in human melanoma cells, that Sox10 promotes neural crest stem cell properties, cell proliferation and cell survival.

Friedhelm Hildebrandt, Agata Smogorzewska and colleagues show that mutations in the DNA repair gene FAN1 cause karyomegalic interstitial nephritis. These findings implicate deficient DNA damage response signaling in the pathophysiology of renal fibrosis.

The tumour suppressor protein VHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, is found at the mitotic spindle in mammalian cells. VHL inactivation leads to unstable astral microtubules and spindle misorientation as well as to reduced levels of Mad2, resulting in spindle checkpoint weakening and genomic instability.

Levi Garraway and colleagues report exome sequencing of 112 prostate adenocarcinomas and matched normal tissues. They identify novel recurrent mutations in several genes, including MED12, FOXA1 and SPOP. They find that tumors harboring SPOP mutations lack the TMPRSS2-ERG fusion or other ETS rearrangements, supporting the hypothesis that SPOP mutation is an early driver event in prostate tumorigenesis.

Roman Thomas and colleagues report exome sequencing of 29 small-cell lung cancers (SCLCs), 2 SCLC genomes and transcriptomes of 15 SCLCs. They identify recurrent mutations in the CREBBP, EP300 and MLL genes encoding histone modifiers. They identify mutations in SLIT2 and EPHA7, which have a role in axon guidance and cell migration, and focal amplifications of FGFR1.