Genomic deletion of tumor suppressor genes can also result in loss of nearby genes that force tumor cells to utilize compensatory pathways to sustain viability. This observation has led to interest in the concept of “collateral lethality,” which aims to therapeutically target these compensatory mechanisms to open more treatment strategies for patients. Achreja and colleagues developed the collateral lethal gene identification via metabolic flux (CLIM) approach to identify MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumors. They identified 19p13.3, containing the ubiquinol-cytochrome C reductase, complex III subunit XI (UQCR11) gene, as the most prevalent deletion in high-grade serous ovarian carcinoma. As UQCR11 encodes part of the electron transport chain (ETC), the authors hypothesized that ovarian cancers with 19p13.3 deletions have ETC impairments and rely on other metabolic pathways to maintain energy requirements. Using multi-objective metabolic flux analysis, they identified methylenetetrahydrofolate dehydrogenase (MTHFD2) as a dependency in cells with 19p13.3 loss. Strikingly, MTHFD2 utilized a noncanonical oxidative function to provide mitochondrial NAD+ in UQCR11/19p13.3-deleted cells. Functionally, MTHFD2 knockdown resulted in selective remission of UQCR11-deleted ovarian cell lines in vitro and in vivo and may be a novel and promising cancer target.Expert Commentary: Using an innovative approach, the authors identify a novel function of MTHFD2 and present it as a promising cancer target in ovarian cancers with UQCR11/19p13.3 deletions.Achreja A, Yu T, Mittal A, Choppara S, Animasahun O, Nenwani M, et al. Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer. Nat Metab 2022;4:1119-37.Although proteolysis-targeting chimeras (PROTAC) have shown activity preclinically in degrading oncoproteins, they have yet to show activity in the clinic. Marei and colleagues have developed a series of novel proteolysis-targeting antibodies (PROTAB) that tether endogenous cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. A ZNRF3*IGFR1 PROTAB was developed that recruited the E3 ubiquitin ligase ZNRF3 to the IGFR1 receptor and led to colon cancer–specific IGFR1 degradation and growth inhibition. Similar efficacy was seen with HER2 or PD-L1–directed PROTABs.Expert Commentary: This study is one of the first reports of a novel class of therapeutic agents that have the potential to have a significant clinical impact on targeting cellular receptors in cancer.Marei H, Tsai W-TK, Kee Y-S, Ruiz K, He J, Cox C, et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature 2022;610:182-9.Pediatric high-grade gliomas are notoriously difficult to treat and are mutationally distinct from adult gliomas. Multiple subgroups of pediatric gliomas harbor mutations in histones, core proteins that organize DNA. While different “oncohistone” mutations correlate with tumor presentation at different locations within the brain, suggesting different etiologies, it has been a challenge to identify mechanistic differences that can guide selection of precision therapies. Here, Haase and colleagues generate mouse and human cell–based models carrying the G34R mutation in Histone 3.3 (H3.3). These tumors had decreased proliferation and stemness relative to comparators without the histone mutation, and elevated DNA damage and genomic instability. These last two features were proposed to result from compromised DNA repair activity, caused by increased compaction of chromatin when mutant H3.3 was present, thus decreasing accessibility of DNA for repair. Because of this instability, G34-mutant tumors were sensitive to radiation-based therapy and were immunogenic, suggesting therapeutic approaches tailored to this mutational subgroup.Expert Commentary: These results uncover a susceptibility of H3.3-G34R high-grade glioma to a combined therapy of radiation, DNA damage response inhibitors, and STING agonists.Haase S, Banerjee K, Mujeeb AA, Hartlage CS, Nunez FM, Nuñez FJ, et al. H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models. Journal of Clinical Investigation; Published online September 20, 2022; doi: 10.1172/JCI154229.Medulloblastoma can be divided into distinct subgroups based on the neuronal origin of the tumor, but there remain many unresolved questions about the developmental lineages, which these tumors arise from in humans. In two recent studies from Smith and colleagues (1) and Hendrikse and colleagues (2), the authors analyzed single-cell RNA-sequencing gene expression data of the human fetal cerebellum and human medulloblastoma tumors. Both showed that Group 3 medulloblastoma (Grp3MB) arises from the ventricular zone of the rhombic lip, whereas Group 4 medulloblastoma (Grp4MB) arises from the more differentiated subventricular zone (a structure specific to Homo sapiens) in the late first to early second trimester. By pseudotime analysis, aggressive Grp3MB was more undifferentiated whereas Grp4MB arose from a differentiated cell type, likely forming a continuum. Grp4MB was enriched for activating events converging on the core binding factor alpha (CBFA) complex, resulting in a differentiation block. Silencing of OTX2 drove differentiation of Grp3MB cell lines in both studies, suggesting that failure of rhombic lip progenitors to differentiate underlies the cellular origins of non-SHH/WNT medulloblastoma.Expert Commentary: These studies clarify that the two most common forms of childhood medulloblastoma arise from the human rhombic lip. This opens the possibility of identifying oncofetal antigens as potential immunological targets of therapy and may allow for more robust modeling.1. Smith KS, Bihannic L, Gudenas BL, Haldipur P, Tao R, Gao Q, et al. Unified rhombic lip origins of group 3 and group 4 medulloblastoma. Nature 2022;609:1012-20.2. Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, et al. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature 2022;609:1021-28.Polymorphonuclear neutrophils play a seminal role in regulating tumor progression and creation of the premetastatic niche. A study from Deng and colleagues described a novel mechanism in which expression of peptidylarginine deiminase 4 (PAD4) in neutrophils promotes cancer progression. Neutrophil PAD4 controls neutrophil trafficking by regulating the expression of the major chemokine receptor CXCR2. Genetic deletion of PADI4 in neutrophils strongly suppressed the formation of metastatic lesions, associated with decreased neutrophils in both the primary tumor and in lung metastases. Pharmacological inhibition of PAD4 with a novel selective PAD4 inhibitor JBI-589 dramatically downregulated chemokine CXCR2, reduced immune suppressive polymorphonuclear myeloid derived suppressor cells at tumor and metastatic sites, activated T cells, and significantly enhanced the antitumor effects of immunotherapy.Expert Commentary: PAD4 regulates tumor progression by promoting neutrophil migration. Targeting neutrophil PAD4 could provide a new approach for reducing metastatic disease and improving the efficacy of immunotherapy in cancer patients. These results highlight the potential of PAD4 inhibition as a novel treatment approach for cancer.Deng H, Lin C, Garcia-Gerique L, Fu S, Cruz Z, Bonner EE, et al. A novel selective inhibitor JBI-589 targets PAD4-mediated neutrophil migration to suppress tumor progression. Cancer Res 2022;82:3561-72.Previous attempts to identify subtypes and driver mutations of acute lymphoblastic leukemia (ALL) have been limited by a lack of large patient cohorts or have only analyzed a limited portion of the genome. Brady and colleagues report on a multi-institution effort that assembled one of the largest patient cohorts in ALL: 2,288 B-lymphoid and 466 T-lymphoid leukemias from children and young adults. Seventy new putative driver genes were reported among 376 identified, 27 of which had never been seen in any human malignancy. A median of four driver alterations per case were identified, similar to the number seen in adults, which was unexpected given the poorer prognosis of adult ALL. By investigating ploidy as a molecular clock and also driver mutation clonality, this study provides evidence for early, potentially in utero–initiating events. The results suggest the majority of childhood B-ALL subtypes are initiated by aneuploidy or translocation early in life, followed by focal deletions in early childhood enabling lymphoid expansion. The study also provides analysis of the comutation and mutual exclusivity that occurs within each ALL subtype and identifies several new biological pathways in ALL.Expert Commentary: This study highlights that there is still much to learn from the genomic events that contribute to transformation in ALL.Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet 2022;54:1376-89.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.