Highlighted research articles

Baker and colleagues develop GRITIC, a novel Bayesian method for timing complex tumor events. It estimates the timing of clonal gains, accounting for whole genome doublings, using single-sample bulk whole genome sequencing data. Applied to 6,091 primary and metastatic tumors, it revealed that complex copy number states in genomedoubled tumors often arise through non-parsimonious histories. The authors found that genome doublings have a greater impact on the landscape of losses than gains, although late doublings often lead to an increased rate of copy number gains.See article, p. 1810.The etiology of meningiomas, the most common type of intracranial tumor, is poorly understood, as are mechanisms of resistance to standard treatment such as radiotherapy in high-grade tumors. Choudhury, Cady, and colleagues show that NOTCH3+ cells are conserved in the perivascular stem cell niche across vertebrate meningiomas and use single-cell transcriptomic profiling and lineage tracing in mouse models of meningioma to show that these cells drive meningeal tumorigenesis and meningioma resistance to radiotherapy. Inhibition of NOTCH3 with an antibody stabilizing its extracellular negative regulatory region blocks meningioma growth and sensitizes tumors to radiotherapy, suggesting a potential therapeutic strategy for treatment of meningiomas that are resistant to standard therapy.See article, p. 1823.An international collaborative study of childhood γδ T-ALL identified those under 3 years of age to be an extremely high-risk subgroup. The STAG2/LMO2 subtype was enriched in this group, exhibiting distinct gene expression and dual-hit genomic alterations driving STAG2 inactivation and LMO2 activation. STAG2 inactivation perturbs chromatin conformations by altering enhancer-promoter looping, resulting in deregulation of T-cell differentiation genes, and introduces a vulnerability in DNA repair pathways that is targetable by PARP inhibition. Identification of γδ T-ALL, and the STAG2/LMO2 subtype should be incorporated in a diagnostic framework for classification and risk stratification of T-ALL in children.See article, p. 1838.Clonal hematopoiesis (CH) is a common premalignant state but with few identified therapeutic targets. Waarts and colleagues identified genetic vulnerabilities in CH by utilizing an ex vivo co-culture platform to perform unbiased CRISPR screens in mutant hematopoietic stem cells. These studies nominated the histone lysine demethylase KDM3B as a critical dependency in a subset of CH. KDM3B loss rewires the epigenetic landscape specifically in mutant cells, leading to decreased expression of key cytokine receptors and a consequent increased susceptibility of mutant cells to inhibition of downstream JAK signaling. These findings pave the way for therapeutics targeting this epigenetically regulated signaling pathway in CH.See article, p. 1860.The design of chimeric antigen receptors (CARs) is crucial in optimizing CAR T-cell therapies, with costimulatory domains playing critical roles. However, their impact on CAR-engineered natural killer (NK) cells is less studied. Acharya and colleagues investigated various costimulatory domains, using a CD70-targeting CAR, to enhance CAR-NK cell activity. Although NK cells naturally lack CD28, its inclusion as a costimulatory domain significantly improved CAR-NK cell potency. Mechanistically, CD28 linked to CD3ζ recruits kinases that initiate a signaling cascade crucial for CAR-NK cell activation. These findings suggest incorporating CD28 costimulation in CAR-NK cell design could greatly improve their effectiveness in cancer therapies.See article, p. 1879.This study shows that deferiprone, an FDA-approved iron chelator, triggers immune responses against ovarian cancer. Iron accumulation by tumors worsens disease progression and resistance to treatment, but whether disrupting this process impacts anti-cancer immunity is unknown. The research reveals that deferiprone activates molecular stress signals in cancer cells, alerting natural killer cells to attack the tumor. Deferiprone improved survival in preclinical models of ovarian cancer and enhanced the effects of standard chemotherapy. These findings uncover iron accumulation as a critical vulnerability in ovarian cancer cells and suggest that iron chelation could be a novel immunotherapy for ovarian cancer.See article, p. 1901.Therapeutic regimens including the BCL-2 inhibitor venetoclax have been shown to eradicate human leukemia stem cells (LSC); however, resistant subpopulations usually remain. In this study, Sheth and colleagues demonstrate venetoclax-resistant LSCs can be targeted through inhibition of mitochondrial calcium uptake, which decreases oxidative phosphorylation, thereby inducing LSC-specific cell death. Intriguingly, the well-established chemotherapy agent mitoxantrone effectively inhibits mitochondrial calcium uptake at nanomolar concentrations, yielding highly effective eradication of LSCs. These data provide rationale to include low-dose mitoxantrone in therapeutic strategies to overcome venetoclax resistance in AML.See article, p. 1922.Although human telomerase reverse transcriptase (hTERT) promoter mutations occur in approximately 20% of human cancers and are recognized as drivers of hTERT reactivation, the mechanism by which wild-type hTERT promoters in the vast proportion of cancers get reactivated continues to be an unsolved mystery. hTERT promoter mutations are rarely seen in colorectal cancer (CRC), and Shanmugam, Majee, Shi, and colleagues document how high levels of Fe3+-iron cause reactivation hTERT in CRC via the iron sensor Pirin. These results show that dietary factors like metal ions collude with genetic mutations to reactivate wild-type hTERT promoters in a subset of CRCs. These results also provide a molecular mechanism linking iron-rich red meat to increased incidence of CRC.See article, p. 1940.Stromal cells are a source of the cytokine IL33 in the pancreatic cancer microenvironment, a cytokine also expressed by cancer cells. Donahue and colleagues show that ablation of stromal IL33 reduces tumor growth and alleviates immunosuppression, indicating that stromal IL33 expression is functionally important. Further, they show that stromal IL33 is induced by oncogenic KRAS expressing pancreatic cancer cells, through secreted signaling factors such as LIF. This study provides new insight into the mechanisms through which KRAS-mutant cells reprogram their surroundings and identifies IL33 as a key regulator of intercellular signaling between tumor cells, fibroblasts, and immune cells.See article, p. 1964.The patterns of prostate cancer metastasis remain poorly understood. Serio and colleagues apply a recordable barcode to mice with a specific metastatic signature to track prostate cancer spread. Once integrated into the genomes, progressive marks on the barcode from cumulative CRISPR–Cas9 editing enable an inference of cancer clonal architecture together with defining metastatic seeding and migratory trajectories. Although initial metastatic dissemination was often polyclonal, only a small number of aggressive clones capable of spreading further to different sites were identified by their marked barcodes. Metastatic topologies were consistent with human prostate cancer spread.See article, p. 1990.