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Two studies have now provided evidence of differences, dependent on patient sex, in oncogenic features, such as frequencies of driver gene mutations, mutation load and mutational signatures, as well as immune selection.
Gomes et al. show that age-dependent upregulation of levels of the metabolite methylmalonic acid (MMA) in serum from healthy donors can promote tumour progression in mice via SOX4-dependent regulation of cell fate decisions.
Disseminated cancer cells in the cerebrospinal fluid of leptomeningeal metastasis not only face survival on limited resources but must also escape activation of an immune response. Chi et al. suggest cancer cells can accomplish this by outcompeting macrophages for an essential micronutrient, iron.
Li, W., Hu, J., Shi, B. et al. showed that the appropriate phase separation property of the protein AKAP95 was required for its regulation of splicing and expression of cancer-related genes, thereby contributing to tumorigenesis.
Koelwyn et al. investigated the connection between cardiovascular events and cancer progression and found that systemic changes induced by myocardial infarction can promote breast tumour growth and increase the risk of cancer-specific death.
Two papers in Nature Medicine report studies that validate the utility of cell-free methylated DNA analysis for early detection of renal cell carcinomas and diagnosis of central nervous system tumours.
Aitken et al. have used mutagen-induced liver tumours to trace individual strands of the DNA double helix to which damage occurred and correlate this with mutational patterns to inform upon tumour evolution.
Using a rapid mass-spectrometry based approach to analyse aerosol released during surgical cauterization of tumour tissue, Koundouros et al. derived metabolic signatures associated with the tumour genotype. Based on these signatures, they identified a new mechanism by which oncogenic PI3K signalling promotes tumour growth.
Allen, Hiam et al. have used mass cytometry to characterize the immune landscape over time in response to tumour development, demonstrating that tumour growth dynamically alters the systemic immune landscape and that this can be reverted by tumour removal.
Nejman et al. have comprehensively characterized the bacteria present in 1,526 human tumours and their adjacent normal tissues encompassing seven different solid tumour types. Their initial findings suggest that much like the gut microbiome, the tumour microbiome may impact many aspects of tumour biology.
Ostendorf et al. show that germline variants of human APOE play a role in melanoma that is opposite to that in Alzheimer disease, with APOE4 carrier status being associated with reduced melanoma growth in mice and improved outcome in patients with advanced melanoma.
Ting Li, Xinyuan Li et al. determined that REL, a member of the nuclear factor-κB (NF-κB) family of transcription factors, has a key role in generating myeloid-derived suppressor cells (MDSCs) and that targeting REL might be used for cancer immunotherapy.
Normal tissues become colonized by clones, which have acquired somatic mutations in common cancer driver genes. Colom et al. have now shown that the fate of mutagen-exposed oesophageal epithelial cells in mice is governed by the genotype of their neighbours with implications for cancer development.
Morral, Stanisavljevic et al. show that colorectal cancer (CRC) cell hierarchy is based on the capacity to perform biosynthesis. Undifferentiated CRC cells that have high capacity for protein synthesis were found immediately adjacent to the stroma, and this capacity was lost upon differentiation.
Chung et al. studied drivers of obesity-associated pancreatic ductal adenocarcinoma in a leptin-deficient mouse model and identified the hormone cholecystokinin, upregulated in islet beta cells in the context of obesity, to be promoting pancreatic tumorigenesis.
The group of Sangeeta Bhatia have leveraged a set of nanosensors to diagnose lung cancer in mice by detecting and amplifying the activity of dysregulated extracellular proteases, offering a urine-based readout.
Klichinsky et al. have engineered macrophages to express chimeric antigen receptors (CARs) that target their phagocytic activity towards tumour cells. These macrophages (CAR-Ms) reduced tumour burden and prolonged overall survival in mice.
Hoekstra et al. and Thibaut et al., both reporting in Nature Cancer, show that interferon-γ secreted by tumour-reactive T cells diffuses into the tumour microenvironment and acts on remote tumour cells to modify tumour behaviour.
Two studies by Park et al. and Papalarazou et al. explored mechanoresponses of cancer cell metabolism in the lung and pancreas, respectively. They identify distinct mechanisms of adaptation to changes in extracellular matrix stiffness, thereby maintaining the cells’ ability to grow or disseminate.
Yoshida, Gowers et al. examined somatic mutations in normal lung epithelium to better understand the effects of tobacco smoking, and stopping smoking, on normal tissue biology and how these effects relate to lung cancer development.
Zagato et al. have identified bacterial species of the microbiome that are lost during intestinal tumorigenesis. Mouse Faecalibaculum rodentium and its human homologue exert their antitumorigenic effect on cell proliferation through the production of short chain fatty acids.
Ajona et al. have shown that short-term starvation can sensitize lung tumours in mice to the action of immune checkpoint blockade through a reduction in levels of circulating insulin-like growth factor 1 (IGF1).
A recent study from Ralph DeBerardinis’ and Sean Morrison’s labs has found that metastatic melanoma cells upregulate the lactate transporter MCT1 in vivo to manage oxidative stress, which allows them to survive during dissemination.
Sinha et al. systematically mapped genomic alterations in lung tumours from an ethnically unbiased patient cohort and demonstrated a higher frequency of homologous recombination deficiency in tumours from African Americans than European Americans, highlighting the need to include diverse populations in cancer genomics studies.
Gene gating is the tethering of genes to nuclear pores to facilitate rapid nuclear export of transcripts. Scholz et al. show that gene gating of MYC increases nuclear export and overall expression of MYC transcripts in human colon cancer cells.
Lin et al. and Lambo et al. report in-depth therapeutic screening and genomic profiling, respectively, of two types of aggressive paediatric central nervous system tumours, and both groups identify vulnerabilities of these tumours that might be exploited therapeutically.
Moya et al. have uncovered a non-cell autonomous, tumour suppressive mechanism of competition driven by the Hippo pathway effectors YAP and TAZ in peritumoural hepatocytes that limits liver cancer in mice.
Strickley, Messerschmidt et al. show that beta human papilloma virus (β-HPV) infection itself is not causal in cutaneous squamous cell carcinoma (SCC) development in the context of immunosuppression — instead, the loss of β-HPV-mediated T cell immunity promotes SCC.
Two papers report the discovery and preclinical analyses of two different covalent inhibitors of KRAS-G12C (AMG 510 and MRTX849) as well as the first data on the efficacy of these inhibitors in cancer patients.
Research by Chemi at al. highlights the potential of using pulmonary venous circulating tumour cells from patients with NSCLC, collected during tumour resection, to predict relapse and to explore mechanisms of early dissemination.
The microbiome is more than just bacteria. Now, the groups of Deepak Saxena and George Miller at New York University have linked alterations in the fungal component of the pancreatic microbiome, which activate the complement cascade, to pancreatic ductal adenocarcinoma growth and progression
Burr et al. report an evolutionarily conserved, tumour-intrinsic role for Polycomb repressive complex 2 (PRC2) in the epigenetic silencing of MHC class I antigen presentation pathway genes, illustrating that cancer cells can co-opt the immunomodulatory functions of PRC2 to evade immune surveillance.
Morris IV et al. adapted a mouse model of human pancreatic ductal adenocarcinoma and found that p53-dependent metabolic changes restrain tumour progression through α-ketoglutarate accumulation and promotion of a premalignant cell fate.
O’Connor et al. show that gliosis in the brain contributes to the development of central nervous system lymphomas (CNSLs) through the production of the chemokine CCL19 by astrocytes, which in turn promotes CNSL cell retention in the brain.
Using high-resolution proteomics to analyse clinical samples from patients with advanced melanoma, Harel et al. show that the metabolic state of melanoma is associated with changes in antigen presentation-related proteins and thereby with response to immunotherapies.
Ombrato et al. developed a fluorescent labelling system, which uses metastatic cells themselves to directly mark neighbouring cells in vivo and revealed the lung parenchyma to be a previously unrecognized component of the metastatic niche.
Rivadeneira et al. show that treatment of melanoma-bearing mice with the oncolytic Vaccinia virus recruits metabolically dysfunctional CD8+ T cells, which limits tumour regression. Vaccinia-mediated engineered expression of leptin in cancer cells improved responses through metabolic reprogramming of T cells.
In a study published in Cell, Dong et al. employ a genome-scale CRISPR screening approach to identify both known and previously uncharacterized regulators of CD8+ T cell activity, highlighting the utility of this approach for immunotherapeutic target discovery.
Zheng et al. have developed a phage-guided nanoparticle approach to modulate tumour-associated bacterial species and deliver chemotherapy for local release. This strategy was able to suppress tumour growth in mouse models of colorectal cancer.
Boettcher et al. show that missense mutations in the DNA-binding domain of TP53 lead to a dominant-negative effect in leukaemia, where mutant p53, instead of activating de novo transcriptional programmes, inhibits the wild-type protein, thereby driving clonal selection.
In a study published in Cell, Riquelme et al. unravel intratumoural microbial events associated with long-term survival in pancreatic ductal adenocarcinoma and illustrate that tumour microbiome composition, which is influenced by gut–tumour microbial crosstalk, influences the host immune response and natural history.
Yost, Satpathy et al. show that the T cell response to immune checkpoint blockade consists of a repertoire of novel T cell clones, which are distinct from pre-existing exhausted T cell clones, and were not detected in the tumour before treatment.