Activating mutations in the Notch pathway promote tumorigenesis in T-cell leukaemias. Iannis Aifantis and colleagues now find that the same pathway suppresses the development of myeloid leukaemias. Inactivating the pathway in haematopoietic stem cells leads to myeloid disease resembling chronic myelomonocytic leukaemia (CMML), and mutations in Notch pathway genes can be found in patients with CMML. The Notch pathway is shown to suppress a myeloid differentiation program. These findings demonstrate that the Notch pathway exerts both oncogenic and tumour-suppressor functions in the haematopoietic system and regulates critical cell-fate decisions. Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex2. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations3. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.

The urothelium is a specialized epithelium that lines the urinary tract. It consists of three different cell types, namely, basal, intermediate and superficial cells arranged in relatively distinct cell layers. Normally, quiescent, it regenerates fast upon injury, but the regeneration process is not fully understood. Although several reports have indicated the existence of progenitors, their identity and exact topology, as well as their role in key processes such as tissue regeneration and carcinogenesis have not been clarified. Here we show that a minor subpopulation of basal cells, characterized by the expression of keratin 14, possesses self-renewal capacity and also gives rise to all cell types of the urothelium during natural and injury-induced regeneration. Moreover, these cells represent cells of origin of urothelial cancer. Our findings support the hypothesis of basally located progenitors with profound roles in urothelial homoeostasis.

Genome‐wide studies in tumor cells have indicated that chromatin‐modifying proteins are commonly mutated in human cancers. The lysine‐specific methyltransferase 2C (KMT2C/MLL3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT2C activity are deficient in homologous recombination‐mediated double‐strand break DNA repair. Consequently, these cells suffer from substantially higher endogenous DNA damage and genomic instability. Finally, these cells seem to rely heavily on PARP1/2 for DNA repair, and treatment with the PARP1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT2C expression are attractive targets for therapies with PARP1/2 inhibitors.

Therapeutic targeting of tumor cells with drug nanocarriers relies upon successful interaction with membranes and efficient cell internalization. A further consideration is that engineered nanomaterials should not damage healthy tissues upon contact. A critical factor in this process is the external coating of drug delivery nanodevices. Using in silico, in vitro and in vivo studies, we show for the first time that magnetic nanoparticles coated with polyarabic acid have superior imaging, therapeutic, and biocompatibility properties. We demonstrate that polyarabic acid coating allows for efficient penetration of cell membranes and internalization into breast cancer cells. Polyarabic acid also allows reversible loading of the chemotherapeutic drug Doxorubicin, which upon release suppresses tumor growth in vivo in a mouse model of breast cancer. Furthermore, these nanomaterials provide in vivo contrasting properties, which directly compare with commercial gadolinium-based contrasting agents. Finally, we report excellent biocompatibility, as these nanomaterial cause minimal, if any cytotoxicity in vitro and in vivo. We thus propose that magnetic nanodevices coated with polyarabic acid offer a new avenue for theranostics efforts as efficient drug carriers, while providing excellent contrasting properties due to their ferrous magnetic core, which can help the future design of nanomaterials for cancer imaging and therapy.

Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Cancer stem cells (CSCs) are a small subset of tumor cells characterized by self-renewal, increased tumor-initiation capacity, and resistance to conventional therapies. As such, they have been implicated in the etiology of tumor recurrence and have emerged as promising targets for the development of novel therapies. Here, we show that the histone demethylase lysine-specific demethylase 1 (LSD1) plays an important role in the chemoresistance of breast cancer cells. Our data, from a series of in vitro and in vivo assays, advocate for LSD1 being critical in maintaining a pool of tumor-initiating cells that may contribute to the development of drug resistance. Combinatory administration of LSD1 inhibitors and anti-cancer drugs is more efficacious than monotherapy alone in eliminating all tumor cells in a 3D spheroid system. In conclusion, we provide compelling evidence that LSD1 is a key regulator of breast cancer stemness and a potential target for the design of future combination therapies.