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A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

Polycomb group proteins are epigenetic gene silencers that are thought to exist in two biochemically distinct multiprotein complexes, termed PRC-1 and -2. Here, Cao et al.show that EED, a core component of PRC2, interacts with and functions as part of PRC1, thus coordinating the activities of both complexes.

CRISPR screen identifies coactivators of the androgen receptor (AR) complex, including NSD2. NSD2 contributes to AR cistrome reprogramming during prostate cancer progression, and its degradation via a novel PROTAC reduces prostate cancer cell viability in vitro.

Myeloid cell subsets are playing important roles in antitumour immunity, and genes affecting their functions are potential targets for immunotherapy. Here authors show that genomic deletion of Pikfyve in CD11c⁺ cells results in tumour growth inhibition via enhanced antigen presentation and priming of antigen-specific CD8⁺ T cells in a mouse tumor model.

Exome sequencing is used to investigate the role of mutations and copy number aberrations in metastatic castration-resistant prostate cancer, revealing recurrent mutations in multiple chromatin/histone modifying genes, as well as genes involved in androgen signalling.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

New noncoding RNAs can be discovered by assembling transcripts from RNA-Seq data. Prensner et al. apply this approach across >100 prostate cancer samples to find noncoding RNAs that distinguish localized tumors from benign forms of the disease.

Chinnaiyan and colleagues perform a high-throughput compound screen and identify PIKfyve inhibition as a therapeutic strategy to enhance immune checkpoint blockade responses in advanced prostate cancer.

PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.

The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.

Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8⁺ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

LncRNAs have been associated with cancer. Here, the authors carry out a systematic review of lncRNAs in breast cancer and show that DSCAM-AS1is highly expressed in oestrogen receptor positive tumours and enhances cancer through an interaction with hnRNPL; and is also associated with tamoxifen resistance.

Clinical exome and transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site, as part of the Michigan Oncology Sequencing (MI-ONCOSEQ) Program.

Targeted cancer therapy requires knowledge of driver aberrations. Here the authors perform large-scale transcriptome analysis, and show that gene fusions in NRG1, NF1and Hippo pathway genes are recurrent mostly among lung cancers lacking known driver mutations.

The molecular alterations driving anti-androgen resistance in prostate cancer are unclear. Here, the authors show, using a network-based approach, that inhibition of the hexosamine biosynthetic pathway is necessary to develop resistance and that increasing the activity of the pathway enhances the anti-androgen response.

Non-small cell lung cancers (NSCLC) that harbour mutations in KRas can be separated into KRas-dependent and -independent subsets. By analysing transcriptome, proteome and phosphoproteome data from NSCLC cell lines, Balbin et al. show that KRas-dependent cell lines activate the Lck pathway.

ARLNC1 is a newly discovered lncRNA that is induced by androgen receptor (AR) and maintains AR signaling by stabilizing the AR transcript. Knockdown of ARLNC1 suppresses AR expression, AR signaling and prostate cancer growth in vitro and in vivo.

The MLL complex promotes androgen receptor signaling and drives growth of castration resistant prostate cancer

This is an issue edsumm for ng1935. Identification of the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence. It shows that sea surface temperatures near the North Pole increased from roughly 18 degrees Celsius to over 23 degrees Celsius — such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors.

Arul Chinnaiyan and colleagues report that the long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers and predicts poor outcome. Mechanistically, they show that SChLAP1 promotes invasiveness and metastasis and antagonizes the functions of the SWI/SNF chromatin-remodeling complex.

With a flood of cancer genome sequences expected soon, distinguishing 'driver' from 'passenger' mutations will be an important task. Wang et al. describe a bioinformatic method for identifying cancer-associated fusions and apply it to discover a recurrent rearrangement in lung cancer.

Distinct translocation mechanisms and additional translocation partners for ETS genes are found in prostate cancer. This study also provides the first functional evidence that ETS gene deregulation can promote cancer cell invasion in cell lines and pre-malignant prostate lesions in a transgenic mouse model.

A systematic analysis of metabolites in prostate cancer samples has led to the identification of sarcosine as a putative biomarker detectable in urine, which could potentially be used to aid prostate cancer diagnosis. Sarcosine promotes the invasion of prostate cancer cells and may play a role in metastasis.

Comprehensive genomic analyses and mechanistic studies uncover three structural, functional and clinical classes of activating FOXA1 mutations and locus rearrangements in prostate cancer.

Small-molecule compounds that target the BET ___domain in proteins such as BRD4 have recently been identified as potential anticancer agents; here, the efficacy of the BRD4-targeting compound JQ1 is demonstrated in castration-resistant prostate cancer driven by deregulated androgen receptor action.

Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding ___domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro.

Using a combination of new generation long- and short-read sequencing technologies, this study analyses cancer samples for gene fusion transcripts. The approach uncovers transcripts arising from known gene fusions in leukaemia and prostate cancer, as well as newly discovered ones in prostate cancer.

Arul Chinnaiyan and colleagues identify NAB2-STAT6 fusions in 52 of 52 solitary fibrous tumor cases. Overexpression of this fusion induced cell proliferation, which could be suppressed by knockdown of EGR1.

Arul Chinnaiyan and colleagues report the curation of 7,256 RNA sequencing libraries from tumors, normal tissues and cell lines. They find 58,648 lncRNAs, of which 79% are previously unnannotated.

In prostate cancer, the oncogenicity of transcription factor ERG is mediated, in part, by competition with another member of the ETS family, ERF.

Wang et al. characterize the tissue distribution of SARS-CoV-2 viral infection and replication as well as the expression of host cell entry factors in postmortem samples from six patients with COVID-19. They report the co-existence of SARS-CoV-2 infection and host entry factors in multiple pulmonary and non-pulmonary tissues.