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Trumpp and colleagues develop a method to obtain long-term circulating tumor cell-derived organoids from individuals with metastatic breast cancer and identify the neuregulin 1–HER3 axis as important for organoid growth and a promising therapeutic target.

Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential and associated dormancy. Here the authors show that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1, and that decline of netrin-1 production during ageing leads to decreased Neo1 mediated HSC self-renewal.

Interact-omics, a high-throughput cytometry-based framework, resolves the cellular interaction landscape.

A technique that combines retrograde axon tracing with single-cell transcriptomics is used to characterize neurons innervating pancreatic ductal adenocarcinoma and healthy pancreas, providing insight into the role of neural connections in cancer progression.

An integrated single-cell multiomic analysis of complex karyotype acute myeloid leukemia characterizes intratumoral heterogeneity and highlights links to therapeutic sensitivities.

The mechanistic basis for the role of the metabolic enzyme BCAA transaminase 1 (BCAT1) in acute myeloid leukaemias.

Baccin, Al-Sabah, Velten et al. use single-cell and spatially resolved transcriptomics to map the cellular, molecular and spatial organization of the endosteal, sinusoidal and arteriolar bone marrow niches.

Expression of HNF1A and KRT81 stratifies pancreatic ductal adenocarcinoma tumors into different subtypes, and expression of cytochrome P450 3A5 mediates basal and/or drug-induced therapy resistance in each subtype.

The mechanisms of intratumoral subtype heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, the authors analyse PDAC tumours and preclinical models using multi-omics and imaging; they demonstrate that AP1 dichotomy influences tumor plasticity, heterogeneity, and immune response, with potential therapeutic implications.

Proton pump inhibitors (PPIs) are prodrugs that are activated by protonation in the highly acidic environment of the stomach lining. Now, coordination of PPIs to protein-bound zinc ions is revealed as another pathway to PPI activation. Acting as a Lewis acid, the zinc ion facilitates conjugation of the drug to zinc-coordinating cysteine residues.

MYC is an iconic oncogene that has been at the forefront of cancer research since its discovery. Looking back over the history of MYC research provides us with a framework with which to progress in the next 25 years, as outlined in this Timeline.

Understanding the immunological underpinnings of long-term survival in cancer is of high interest. Here, authors dissect the immune parameters of multiple myeloma long-term survivors following a single line of therapy longitudinally, and find sustained changes, including inflammation and impaired immune function.

Velten et al. use single-cell transcriptomics and functional data to map the early lineage commitment of human haematopoietic stem cells as a continuous process of cells passing through transitory states rather than demarcating discrete progenitors.

Double-positive αβ thymocytes undergo negative selection on thymic epithelial cells. Ziegler and colleagues show that TGF-β limits numbers and function of medullary thymic epithelial cells, thus influencing the resultant T cell repertoire.

Haematopoietic stem cells (HSCs) can reside as dormant cells in endosteal niches in the bone marrow, where they are resistant to certain types of chemotherapy. In this article, the authors suggest that by first awakening dormant HSCs to become actively self-renewing cells, this resistance to chemotherapy could be overcome.

Alborzinia et al. report that MYCN-amplified neuroblastoma undergoes ferroptosis in the absence of intracellular cysteine, suggesting a combination of cysteine depletion and concomitant GPX4 inactivation as a potential therapeutic approach.

A xenograft assay facilitates identification of metastasis-initiating cells in the blood of individuals with breast cancer.

The interaction between hematopoietic stem cells and their niche is critical for the lifelong maintenance of the blood system. New research shows that crosstalk between stromal components of the niche mediates secretion of the chemokine CXCL12.

Proferroptotic activity of 7-dehydrocholesterol reductase is shown along with an unexpected prosurvival function of its substrate, 7-dehydrocholesterol, indicating a cell-intrinsic mechanism that could be used by cancer cells to protect phospholipids from oxidative damage and escape ferroptosis.

A blood enhancer cluster forms a highly combinatorial system that allows precise control of Myc expression across normal and leukaemic haematopoietic stem-cell hierarchies.

Hongu et al. find that perivascular macrophages stimulate activation of the pro-metastatic vascular niche via tenascin C stimulation of TLR4 and show that combined TLR4 and VEGF inhibition prevents TNC-mediated metastatic vascular activity.

Cancer stem cells often represent a minor, highly self-renewing population within the tumor mass and are thought to be the only cells required for both initiation and maintenance of disease. The biology of cancer stem cells, the mechanisms of therapy resistance, and potential future therapeutic interventions in the clinical setting are discussed.

The presence of peritoneal metastasis in pancreatic cancers is associated with poor prognosis. Here the authors show that hyaluronan and proteoglycan link protein-1 (HAPLN1) promotes tumour cell plasticity and pro-tumoral immune microenvironment to facilitate peritoneal dissemination in pancreatic cancers.

Leukaemic stem cells drive acute myeloid leukaemia (AML) progression and relapse but they are incompletely characterized. Here, the authors combine single-cell transcriptomics and clonal tracking using nuclear and mitochondrial somatic variants to distinguish healthy, pre-leukaemic and leukaemic stem cells in AML.

Müller-Tidow and colleagues demonstrate that hotspot DNMT3A mutations found in clonal hematopoiesis and acute myeloid leukemia render cancer cells sensitive to the DNMT1 inhibitor azacitidine through focal DNA demethylation, viral mimicry and interferon activation.

How cancer cells engage the microenvironment to establish metastasis is poorly understood. Here, the authors show that CXCR3-expressing breast cancer cells secrete IL-1 to induce a paracrine crosstalk with fibroblasts in the lung, which involves CXCL9/10 production and results in colonization of the lung.

Singh and colleagues show that PDAC phenotypic plasticity is regulated via AP1 enhancer remodeling and modulated by TNF-α⁺ macrophages and pharmacological inhibition of the BRD4–cJUN–CCL2–TNF-α axis restores favorable PDAC subtypes and prognosis.

Saçma, Pospiech and co-workers show that sinusoidal niches are uniquely preserved on ageing, that they are the predominant niche for label-retaining (LR)-HSCs in aged mice and display higher reconstitution capacity compared with non-LR HSCs.

Owen Sansom and colleagues show that conditional deletion of Pten specifically from the small intestinal epithelium in mice does not disrupt normal tissue architecture, but in the context of Apc deficiency leads to rapid development of adenocarcinoma. These findings suggest that Pten does not serve a rate-limiting, intrinsic role in regulating normal intestinal stem cell physiology.

Polarisation of metastasising cancer cells in circulation has not been investigated before. Here the authors identify single cell polarity as a distinct polarisation state of single cells in liquid phase, and show that perturbing single cell polarity affects attachment, adhesion, transmigration and metastasis in vitro and in vivo.

Haas, Velten and colleagues use single-cell multiomics of human blood and bone marrow to generate a reference map allowing the quantitative linking of cytometry and proteo-genomic information.

Pancreatic cancer cells may develop resistance to KRAS inhibitors due to activation of compensatory pathways. In this study, the authors demonstrate that KRAS is dispensable in a subset of pancreatic cancer and that PI3K signalling may have an important role in mediating tumor growth following KRAS inhibition.

Leukaemic stem cells in acute myeloid leukaemia are defined by a lack of expression of NKG2D ligands, which mediates their ability to evade surveillance by NK cells.

This paper shows that in response to treatment of mice with interferon-α (IFNα), haematopoietic stem cells exit the dormant stage and enter an active cell cycle, The data may help to clarify the clinical effects of IFNa on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.

Using a multi-tier scRNA-seq and CRISP-seq approach, Giladi et al. define a transcriptional signature for the naive haematopoietic stem cell state, and follow progenitor plasticity and fate commitment under the influence of cytokines and growth factors.

Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.