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Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers. Breast cancer tumors originating from mammary luminal epithelial cells are highly heterogeneous. Here, the authors show MYC-driven tumor initiation is reliant on cell reprogramming via an epigenetic program which leads to mammary luminal epithelial cells acquiring basal/stem cell-like properties.

Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.

Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity. The Myc transcription factor is a major regulator of stem cell (SC) self-renewal and pluripotency but how this integrates signals from other pathways is unclear. Here, the authors show that Myc activation triggers epigenetic memory in self renewing embryonic SCs via PRC2-mediated potentiation of the Wnt pathway.

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network. The maintenance of cell identity and/or cell lineage commitment relies on the interplay of multiple factors including signaling pathways, transcription factors, and the epigenetic machinery. These regulatory modules are strongly interconnected and they influence the pattern of gene expression of stem cells, thus guiding their cellular fate. Embryonic stem cells (ESCs) represent an invaluable tool to study this interplay, being able to indefinitely self-renew and to differentiate towards all three embryonic germ layers in response to developmental cues. In this review, we highlight those mechanisms of signaling to chromatin, which regulate chromatin modifying enzymes, histone modifications, and nucleosome occupancy. In addition, we report the molecular mechanisms through which signaling pathways affect both the epigenetic and the transcriptional state of ESCs, thereby influencing their cell identity. We propose that the dynamic nature of oscillating signaling and the different regulatory network topologies through which those signals are encoded determine specific gene expression programs, leading to the fluctuation of ESCs among multiple pluripotent states or to the establishment of the necessary conditions to exit pluripotency.

The original version of this Article contained an error in the spelling of the author Miriam Gaggianesi, which was incorrectly given as Miriam Giaggianesi. Furthermore, the affiliation details for Gabriella Gaudioso, Valentina Vaira, and Silvano Bosari incorrectly omitted ‘Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy’. Finally, the affiliation details for Alice Turdo, Miriam Gaggianesi, Aurora Chinnici and Elisa Lipari were incorrectly given as ‘Dipartimento di Biotecnologie Mediche e Medicina Legale Sezione di Biochimica Medica, Facoltà di Medicina e Chirurgia, Policlinico “P.Giaccone”, Università di Palermo, Palermo, 90127, Italy’. The correct affiliation is ‘Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, 90127, Italy’. These errors have now been corrected in both the PDF and HTML versions of the Article.

BackgroundGlioblastoma multiforme (GBM) is an incurable glial tumor affecting the central nervous system. The reported median survival and the percentage of patient surviving up to 2-years in the unfavorable patients’ subgroup with unmethylated (u)MGMT promoter is 12.7 months and less than then 15% (Stupp et al., 2009), respectively. Despite immunotherapies being able to slow or eradicate numerous tumors, even those metastasized to the brain, none so far have extended survival in GBM.MethodsWe have developed a personalized hematopoietic stem cell-based immunotherapy platform delivering immunotherapeutic payloads into the TME through a subset of tumor infiltrating macrophages. Specifically, Temferon has been designed to deliver IFN-α2 within the TME by Tie-2 expressing macrophages (TEMs). Temferon is currently under testing in an open-label, Phase 1/2a dose-escalation study (NCT03866109) evaluating its safety, and biological activity in up to 27 newly diagnosed GBM patients with uMGMT. Temferon is administered by ASCT after the RTx treatment without the concurrent administration of Temozolomide, whose survival benefit is known to be marginal in the uMGMT population.ResultsAs of June 2023, 4 incremental doses of Temferon (0.5–3.0 x106 cells/kg) have been tested across 21 patients (median age at enrolment 57) assigned to seven cohorts. Median Overall Survival (OS)) after 1st surgery is 15 months (5–40 months). The haematological recovery occurred in all the patients irrespective of dose administered. The percentage of transduced cells found in the BM, reached for the highest dose tested up to the 50% at 1 month and persisted at detectable level in the long-term. Very low median concentrations of IFNα were detected in the plasma, indicating tight regulation of vector expression. Notably, as predicted by TEMs biological behaviour, in the CSF the concentration of IFNa increased concomitantly to evidence of disease progression suggesting increase tumor recruitment of TEMs and subsequent release of IFNa . The 57% of the treated patients underwent a 2nd-line treatment (either pharmacological or surgical) with an interim survival rate at 2-years of 28% (5 of 18 patients; 3 patients excluded as follow-up is below 12 months), which is higher than that reported in literature (15%). One out of the surviving patients was enrolled in a long-term follow-up study and survived up to 3 years after surgery without any 2nd-line therapy added for 2 years.ConclusionsThese data provide initial evidence on Temferon potential to counteract disease progression and improve the survival of uMGMT GBM patients.

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog–activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch +/– SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch +/– SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

This study established long‐term self‐renewing prostate cancer stem cell (PCSC) lines from the different stages of transgenic adenocarcinoma of the mouse prostate (TRAMP) progression by application of the neurosphere assay. It was found that TRAMP‐derived PCSCs represent a novel and valuable preclinical model for elucidating the pathogenetic mechanisms leading to prostate adenocarcinoma and for the identification of molecular mediators to be pursued as therapeutic targets. The relevant social and economic impact of prostate adenocarcinoma, one of the leading causes of death in men, urges critical improvements in knowledge of the pathogenesis and cure of this disease. These can also be achieved by implementing in vitro and in vivo preclinical models by taking advantage of prostate cancer stem cells (PCSCs). The best‐characterized mouse model of prostate cancer is the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice develop a progressive lesion called prostatic intraepithelial neoplasia that evolves into adenocarcinoma (AD) between 24 and 30 weeks of age. ADs often metastasize to lymph nodes, lung, bones, and kidneys. Eventually, approximately 5% of the mice develop an androgen‐independent neuroendocrine adenocarcinoma. Here we report the establishment of long‐term self‐renewing PCSC lines from the different stages of TRAMP progression by application of the neurosphere assay. Stage‐specific prostate cell lines were endowed with the critical features expected from malignant bona fide cancer stem cells, namely, self‐renewal, multipotency, and tumorigenicity. Notably, transcriptome analysis of stage‐specific PCSCs resulted in the generation of well‐defined, meaningful gene signatures, which identify distinct stages of human tumor progression. As such, TRAMP‐derived PCSCs represent a novel and valuable preclinical model for elucidating the pathogenetic mechanisms leading to prostate adenocarcinoma and for the identification of molecular mediators to be pursued as therapeutic targets.

Glioblastoma (GBM) represents the most common and aggressive tumor of the brain. Despite the fact that several studies have recently addressed the molecular mechanisms underlying the disease, its etiology and pathogenesis are still poorly understood. GBM displays poor prognosis and its resistance to common therapeutic approaches makes it a highly recurrent tumor. Several studies have identified a subpopulation of tumor cells, known as GBM cancer stem cells (CSCs) characterized by the ability of self-renewal, tumor initiation and propagation. GBM CSCs have been shown to survive GBM chemotherapy and radiotherapy. Thus, targeting CSCs represents a promising approach to treat GBM. Recent evidence has shown that GBM is characterized by a dysregulated expression of microRNA (miRNAs). In this study we have investigated the difference between human GBM CSCs and their paired autologous differentiated tumor cells. Array-based profiling and quantitative Real-Time PCR (qRT-PCR) were performed to identify miRNAs differentially expressed in CSCs. The Cancer Genome Atlas (TCGA) data were also interrogated, and functional interpretation analysis was performed. We have identified 14 miRNAs significantly differentially expressed in GBM CSCs (p < 0.005). MiR-21 and miR-95 were among the most significantly deregulated miRNAs, and their expression was also associated to patient survival. We believe that the data provided here carry important implications for future studies aiming at elucidating the molecular mechanisms underlying GBM.

Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes resulted difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Over-expression of MYC induces transcriptional repression of lineage specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.