bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry
Authors: Smyth Lillian M. , Zhou Qin , Nguyen Bastien , Yu Celeste , Lepisto Eva M. , Arnedos Monica , Hasset Michael J. , Lenoue-Newton Michele L. , Blauvelt Natalie , Dogan Semih , Micheel Christine M. , Wathoo Chetna , Horlings Hugo , Hudecek Jan , Gross Benjamin E. , Kundra Ritika , Sweeney Shawn M. , Gao JianJiong , Schultz Nikolaus , Zarski Andrew , Gardos Stuart M. , Lee Jocelyn , Sheffler-Collins Seth , Park Ben H. , Sawyers Charles L. , André Fabrice , Levy Mia , Meric-Bernstam Funda , Bedard Philippe L. , Iasonos Alexia , Schrag Deborah , Hyman David M.
Published: April 2023

Abstract
AKT inhibitors have promising activity in AKT1E17K-mutant estrogen receptor (ER)–positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1E17K-mutant (n = 153) and AKT1–wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1–wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology.
Significance:
We delineate the natural history of a rare genomically distinct cancer, AKT1E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.

See related commentary by Castellanos and Baxi, p. 490.
Data from Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
Authors: Dong Zhen , Zhang Guoxin , Qu Meng , Gimple Ryan C. , Wu Qiulian , Qiu Zhixin , Prager Briana C. , Wang Xiuxing , Kim Leo J.Y. , Morton Andrew R. , Dixit Deobrat , Zhou Wenchao , Huang Haidong , Li Bin , Zhu Zhe , Bao Shideng , Mack Stephen C. , Chavez Lukas , Kay Steve A. , Rich Jeremy N.
Published: April 2023

Abstract
Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated glioblastoma cells (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell-cycle arrest and apoptosis. Chromatin immunoprecipitation revealed that BMAL1 preferentially bound metabolic genes and was associated with active chromatin regions in GSCs compared with neural stem cells. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of tricarboxylic acid cycle enzymes. Small-molecule agonists of two independent BMAL1–CLOCK negative regulators, the cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of cryptochrome and REV-ERB agonists induced synergistic antitumor efficacy. Collectively, these findings show that GSCs co-opt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.
Significance:
Cancer stem cells are highly malignant tumor-cell populations. We demonstrate that GSCs selectively depend on circadian regulators, with increased binding of the regulators in active chromatin regions promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting of circadian networks specifically disrupted cancer stem cell growth and self-renewal.

This article is highlighted in the In This Issue feature, p. 1469
Data from A Mutation in Histone H2B Represents a New Class of Oncogenic Driver
Authors: Bennett Richard L. , Bele Aditya , Small Eliza C. , Will Christine M. , Nabet Behnam , Oyer Jon A. , Huang Xiaoxiao , Ghosh Rajarshi P. , Grzybowski Adrian T. , Yu Tao , Zhang Qiao , Riva Alberto , Lele Tanmay P. , Schatz George C. , Kelleher Neil L. , Ruthenburg Alexander J. , Liphardt Jan , Licht Jonathan D.
Published: April 2023

Abstract
By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression.
Significance:
Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.

See related commentary by Sarthy and Henikoff, p. 1346.

This article is highlighted in the In This Issue feature, p. 1325
Data from CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation
Authors: Rasool Reyaz ur , Natesan Ramakrishnan , Deng Qu , Aras Shweta , Lal Priti , Sander Effron Samuel , Mitchell-Velasquez Erick , Posimo Jessica M. , Carskadon Shannon , Baca Sylvan C. , Pomerantz Mark M. , Siddiqui Javed , Schwartz Lauren E. , Lee Daniel J. , Palanisamy Nallasivam , Narla Goutham , Den Robert B. , Freedman Matthew L. , Brady Donita C. , Asangani Irfan A.
Published: April 2023

Abstract
Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo, THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.
Significance:
Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.

See related commentary by Russo et al., p. 1490.

This article is highlighted in the In This Issue feature, p. 1469
Data from Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
Authors: Zhang Shuang , Iyer Sonia , Ran Hao , Dolgalev Igor , Gu Shengqing , Wei Wei , Foster Connor J.R. , Loomis Cynthia A. , Olvera Narciso , Dao Fanny , Levine Douglas A. , Weinberg Robert A. , Neel Benjamin G.
Published: April 2023

Abstract
The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)–proficient (Trp53−/−;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Trp53−/−;Brca1−/−;MycOE), and unclassified (Trp53−/−;Pten−/−;Nf1−/−) organoids revealed differences in in vitro properties (proliferation, differentiation, and “secretome”), copy-number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, and evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T cell–dependent responses in Trp53−/−;Ccne1OE;Akt2OE;Kras HGSC; in contrast, Trp53−/−;Pten−/−;Nf1−/− tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics.
Significance:
The lack of genetically informed, diverse, immunocompetent models poses a major barrier to therapeutic development for many malignancies. Using engineered fallopian tube organoids to study the cell-autonomous and cell-nonautonomous effects of specific combinations of mutations found in HGSC, we suggest an effective combination treatment for the currently intractable CCNE1-amplified subgroup.

This article is highlighted in the In This Issue feature, p. 211
Data from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes
Authors: Miyabayashi Koji , Baker Lindsey A. , Deschênes Astrid , Traub Benno , Caligiuri Giuseppina , Plenker Dennis , Alagesan Brinda , Belleau Pascal , Li Siran , Kendall Jude , Jang Gun Ho , Kawaguchi Risa Karakida , Somerville Tim D.D. , Tiriac Hervé , Hwang Chang-Il , Burkhart Richard A. , Roberts Nicholas J. , Wood Laura D. , Hruban Ralph H. , Gillis Jesse , Krasnitz Alexander , Vakoc Christopher R. , Wigler Michael , Notta Faiyaz , Gallinger Steven , Park Youngkyu , Tuveson David A.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC.
Significance:
Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.

See related commentary by Pickering and Morton, p. 1448.

This article is highlighted in the In This Issue feature, p. 1426
Data from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
Authors: Ngo Bryan , Kim Eugenie , Osorio-Vasquez Victoria , Doll Sophia , Bustraan Sophia , Liang Roger J. , Luengo Alba , Davidson Shawn M. , Ali Ahmed , Ferraro Gino B. , Fischer Grant M. , Eskandari Roozbeh , Kang Diane S. , Ni Jing , Plasger Ariana , Rajasekhar Vinagolu K. , Kastenhuber Edward R. , Bacha Sarah , Sriram Roshan K. , Stein Benjamin D. , Bakhoum Samuel F. , Snuderl Matija , Cotzia Paolo , Healey John H. , Mainolfi Nello , Suri Vipin , Friedman Adam , Manfredi Mark , Sabatini David M. , Jones Drew R. , Yu Min , Zhao Jean J. , Jain Rakesh K. , Keshari Kayvan R. , Davies Michael A. , Vander Heiden Matthew G. , Hernando Eva , Mann Matthias , Cantley Lewis C. , Pacold Michael E.
Published: April 2023

Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis.
Significance:
Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.

This article is highlighted in the In This Issue feature, p. 1241
Data from First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors
Authors: Yap Timothy A. , Tan David S.P. , Terbuch Angelika , Caldwell Reece , Guo Christina , Goh Boon Cher , Heong Valerie , Haris Noor R. Md. , Bashir Saira , Drew Yvette , Hong David S. , Meric-Bernstam Funda , Wilkinson Gary , Hreiki Joseph , Wengner Antje M. , Bladt Friedhelm , Schlicker Andreas , Ludwig Matthias , Zhou Yinghui , Liu Li , Bordia Sonal , Plummer Ruth , Lagkadinou Eleni , de Bono Johann S.
Published: April 2023

Abstract
Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients with advanced solid tumors. The MTD was 40 mg twice daily 3 days on/4 days off. Most common adverse events were manageable and reversible hematologic toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg twice daily. Overall, BAY 1895344 is well tolerated, with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.
Significance:
Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.

See related commentary by Italiano, p. 14.

This article is highlighted in the In This Issue feature, p. 1
Data from Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment
Authors: Chen Xufeng , Glytsou Christina , Zhou Hua , Narang Sonali , Reyna Denis E. , Lopez Andrea , Sakellaropoulos Theodore , Gong Yixiao , Kloetgen Andreas , Yap Yoon Sing , Wang Eric , Gavathiotis Evripidis , Tsirigos Aristotelis , Tibes Raoul , Aifantis Iannis
Published: April 2023

Abstract
The BCL2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL2 inhibitor, has received FDA approval for the treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of venetoclax resistance, and its ablation sensitizes AML to venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent venetoclax resistance.
Significance:
A genome-wide CRISPR/Cas9 screen reveals genes involved in mitochondrial biological processes participate in the acquisition of venetoclax resistance. Loss of the mitochondrial protein CLPB leads to structural and functional defects of mitochondria, hence sensitizing AML cells to apoptosis. Targeting CLPB synergizes with venetoclax and the venetoclax/azacitidine combination in AML in a p53-independent manner.

See related commentary by Savona and Rathmell, p. 831.

This article is highlighted in the In This Issue feature, p. 813
Data from Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade
Authors: Kohlhapp Frederick J. , Haribhai Dipica , Mathew Rebecca , Duggan Ryan , Ellis Paul A. , Wang Rui , Lasater Elisabeth A. , Shi Yan , Dave Nimita , Riehm Jacob J. , Robinson Valerie A. , Do An D. , Li Yijin , Orr Christine J. , Sampath Deepak , Raval Aparna , Merchant Mark , Bhathena Anahita , Salem Ahmed Hamed , Hamel Keith M. , Leverson Joel D. , Donawho Cherrie , Pappano William N. , Uziel Tamar
Published: April 2023

Abstract
The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti–PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy.
Significance:
The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency–approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.

This article is highlighted in the In This Issue feature, p. 1
Data from A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency
Authors: Le Naour Julie , Liu Peng , Zhao Liwei , Adjemian Sandy , Sztupinszki Zsofia , Taieb Julien , Mulot Claire , Silvin Aymeric , Dutertre Charles-Antoine , Ginhoux Florent , Sauvat Allan , Cerrato Giulia , Castoldi Francesca , Martins Isabelle , Stoll Gautier , Paillet Juliette , Mangane Khady , Richter Cornelia , Kepp Oliver , Maiuri Maria Chiara , Pietrocola Federico , Vandenabeele Peter , André Fabrice , Delaloge Suzette , Szallasi Zoltan , Laurent-Puig Pierre , Zucman-Rossi Jessica , Zitvogel Laurence , Pol Jonathan G. , Vacchelli Erika , Kroemer Guido
Published: April 2023

Abstract
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.
Significance:
The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect.

This article is highlighted in the In This Issue feature, p. 211
Data from The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells
Authors: Dixit Deobrat , Prager Briana C. , Gimple Ryan C. , Poh Hui Xian , Wang Yang , Wu Qiulian , Qiu Zhixin , Kidwell Reilly L. , Kim Leo J.Y. , Xie Qi , Vitting-Seerup Kristoffer , Bhargava Shruti , Dong Zhen , Jiang Li , Zhu Zhe , Hamerlik Petra , Jaffrey Samie R. , Zhao Jing Crystal , Wang Xiuxing , Rich Jeremy N.
Published: April 2023

Abstract
Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA immunoprecipitation followed by sequencing and transcriptome analysis, finding transcripts marked by m6A often upregulated compared with normal neural stem cells (NSC). Interrogating m6A regulators, GSCs displayed preferential expression, as well as in vitro and in vivo dependency, of the m6A reader YTHDF2, in contrast to NSCs. Although YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized MYC and VEGFA transcripts in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2–MYC axis in GSCs. The IGF1/IGF1R inhibitor linsitinib preferentially targeted YTHDF2-expressing cells, inhibiting GSC viability without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2–MYC–IGFBP3 axis as a specific and novel therapeutic target in glioblastoma.
Significance:
Epitranscriptomics promotes cellular heterogeneity in cancer. RNA m6A landscapes of cancer and NSCs identified cell type–specific dependencies and therapeutic vulnerabilities. The m6A reader YTHDF2 stabilized MYC mRNA specifically in cancer stem cells. Given the challenge of targeting MYC, YTHDF2 presents a therapeutic target to perturb MYC signaling in glioblastoma.

This article is highlighted in the In This Issue feature, p. 211
Data from Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis
Authors: Kim Michael P. , Li Xinqun , Deng Jenying , Zhang Yun , Dai Bingbing , Allton Kendra L. , Hughes Tara G. , Siangco Christian , Augustine Jithesh J. , Kang Ya'an , McDaniel Joy M. , Xiong Shunbin , Koay Eugene J. , McAllister Florencia , Bristow Christopher A. , Heffernan Timothy P. , Maitra Anirban , Liu Bin , Barton Michelle C. , Wasylishen Amanda R. , Fleming Jason B. , Lozano Guillermina
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
Significance:
Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.

This article is highlighted in the In This Issue feature, p. 1861
Data from Discovery of Candidate DNA Methylation Cancer Driver Genes
Authors: Pan Heng , Renaud Loïc , Chaligne Ronan , Bloehdorn Johannes , Tausch Eugen , Mertens Daniel , Fink Anna Maria , Fischer Kirsten , Zhang Chao , Betel Doron , Gnirke Andreas , Imielinski Marcin , Moreaux Jérôme , Hallek Michael , Meissner Alexander , Stilgenbauer Stephan , Wu Catherine J. , Elemento Olivier , Landau Dan A.
Published: April 2023

Abstract
Epigenetic alterations, such as promoter hypermethylation, may drive cancer through tumor suppressor gene inactivation. However, we have limited ability to differentiate driver DNA methylation (DNAme) changes from passenger events. We developed DNAme driver inference–MethSig–accounting for the varying stochastic hypermethylation rate across the genome and between samples. We applied MethSig to bisulfite sequencing data of chronic lymphocytic leukemia (CLL), multiple myeloma, ductal carcinoma in situ, glioblastoma, and to methylation array data across 18 tumor types in TCGA. MethSig resulted in well-calibrated quantile–quantile plots and reproducible inference of likely DNAme drivers with increased sensitivity/specificity compared with benchmarked methods. CRISPR/Cas9 knockout of selected candidate CLL DNAme drivers provided a fitness advantage with and without therapeutic intervention. Notably, DNAme driver risk score was closely associated with adverse outcome in independent CLL cohorts. Collectively, MethSig represents a novel inference framework for DNAme driver discovery to chart the role of aberrant DNAme in cancer.
Significance:
MethSig provides a novel statistical framework for the analysis of DNA methylation changes in cancer, to specifically identify candidate DNA methylation driver genes of cancer progression and relapse, empowering the discovery of epigenetic mechanisms that enhance cancer cell fitness.

This article is highlighted in the In This Issue feature, p. 2113
Data from Discovery and Features of an Alkylating Signature in Colorectal Cancer
Authors: Gurjao Carino , Zhong Rong , Haruki Koichiro , Li Yvonne Y. , Spurr Liam F. , Lee-Six Henry , Reardon Brendan , Ugai Tomotaka , Zhang Xuehong , Cherniack Andrew D. , Song Mingyang , Van Allen Eliezer M. , Meyerhardt Jeffrey A. , Nowak Jonathan A. , Giovannucci Edward L. , Fuchs Charles S. , Wu Kana , Ogino Shuji , Giannakis Marios
Published: April 2023

Abstract
Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression.
Significance:
Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D.

This article is highlighted in the In This Issue feature, p. 2355
Data from Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis
Authors: Li Jun , Duran Mercedes A. , Dhanota Ninjit , Chatila Walid K. , Bettigole Sarah E. , Kwon John , Sriram Roshan K. , Humphries Matthew P. , Salto-Tellez Manuel , James Jacqueline A. , Hanna Matthew G. , Melms Johannes C. , Vallabhaneni Sreeram , Litchfield Kevin , Usaite Ieva , Biswas Dhruva , Bareja Rohan , Li Hao Wei , Martin Maria Laura , Dorsaint Princesca , Cavallo Julie-Ann , Li Peng , Pauli Chantal , Gottesdiener Lee , DiPardo Benjamin J. , Hollmann Travis J. , Merghoub Taha , Wen Hannah Y. , Reis-Filho Jorge S. , Riaz Nadeem , Su Shin-San Michael , Kalbasi Anusha , Vasan Neil , Powell Simon N. , Wolchok Jedd D. , Elemento Olivier , Swanton Charles , Shoushtari Alexander N. , Parkes Eileen E. , Izar Benjamin , Bakhoum Samuel F.
Published: April 2023

Abstract
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS–STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti–PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway.
Significance:
Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.

This article is highlighted in the In This Issue feature, p. 995
Data from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
Authors: Pikman Yana , Tasian Sarah K. , Sulis Maria Luisa , Stevenson Kristen , Blonquist Traci M. , Apsel Winger Beth , Cooper Todd M. , Pauly Melinda , Maloney Kelly W. , Burke Michael J. , Brown Patrick A. , Gossai Nathan , McNeer Jennifer L. , Shukla Neerav N. , Cole Peter D. , Kahn Justine M. , Chen Jing , Barth Matthew J. , Magee Jeffrey A. , Gennarini Lisa , Adhav Asmani A. , Clinton Catherine M. , Ocasio-Martinez Nicole , Gotti Giacomo , Li Yuting , Lin Shan , Imamovic Alma , Tognon Cristina E. , Patel Tasleema , Faust Haley L. , Contreras Cristina F. , Cremer Anjali , Cortopassi Wilian A. , Garrido Ruiz Diego , Jacobson Matthew P. , Dharia Neekesh V. , Su Angela , Robichaud Amanda L. , Saur Conway Amy , Tarlock Katherine , Stieglitz Elliot , Place Andrew E. , Puissant Alexandre , Hunger Stephen P. , Kim Annette S. , Lindeman Neal I. , Gore Lia , Janeway Katherine A. , Silverman Lewis B. , Tyner Jeffrey W. , Harris Marian H. , Loh Mignon L. , Stegmaier Kimberly
Published: April 2023

Abstract
Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials.
Significance:
Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.

See related commentary by Bornhauser and Bourquin, p. 1322.

This article is highlighted in the In This Issue feature, p. 1307
Data from Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
Authors: Pullarkat Vinod A. , Lacayo Norman J. , Jabbour Elias , Rubnitz Jeffrey E. , Bajel Ashish , Laetsch Theodore W. , Leonard Jessica , Colace Susan I. , Khaw Seong Lin , Fleming Shaun A. , Mattison Ryan J. , Norris Robin , Opferman Joseph T. , Roberts Kathryn G. , Zhao Yaqi , Qu Chunxu , Badawi Mohamed , Schmidt Michelle , Tong Bo , Pesko John C. , Sun Yan , Ross Jeremy A. , Vishwamitra Deeksha , Rosenwinkel Lindsey , Kim Su Young , Jacobson Amanda , Mullighan Charles G. , Alexander Thomas B. , Stock Wendy
Published: April 2023

Abstract
Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
Significance:
In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.

See related commentary by Larkin and Byrd, p. 1324.

This article is highlighted in the In This Issue feature, p. 1307
Data from Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, EGFR-Mutated Non–Small Cell Lung Cancer
Authors: Jänne Pasi A. , Baik Christina , Su Wu-Chou , Johnson Melissa L. , Hayashi Hidetoshi , Nishio Makoto , Kim Dong-Wan , Koczywas Marianna , Gold Kathryn A. , Steuer Conor E. , Murakami Haruyasu , Yang James Chih-Hsin , Kim Sang-We , Vigliotti Michele , Shi Rong , Qi Zhenhao , Qiu Yang , Zhao Lihui , Sternberg David , Yu Channing , Yu Helena A.
Published: April 2023

Abstract
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers.
Significance:
In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.

See related commentary by Lim et al., p. 16.

This article is highlighted in the In This Issue feature, p. 1
Data from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem
Authors: McLeod Clay , Gout Alexander M. , Zhou Xin , Thrasher Andrew , Rahbarinia Delaram , Brady Samuel W. , Macias Michael , Birch Kirby , Finkelstein David , Sunny Jobin , Mudunuri Rahul , Orr Brent A. , Treadway Madison , Davidson Bob , Ard Tracy K. , Chiao Arthur , Swistak Andrew , Wiggins Stephanie , Foy Scott , Wang Jian , Sioson Edgar , Wang Shuoguo , Michael J. Robert , Liu Yu , Ma Xiaotu , Patel Aman , Edmonson Michael N. , Wilkinson Mark R. , Frantz Andrew M. , Chang Ti-Cheng , Tian Liqing , Lei Shaohua , Islam S.M. Ashiqul , Meyer Christopher , Thangaraj Naina , Tater Pamella , Kandali Vijay , Ma Singer , Nguyen Tuan , Serang Omar , McGuire Irina , Robison Nedra , Gentry Darrell , Tang Xing , Palmer Lance E. , Wu Gang , Suh Ed , Tanner Leigh , McMurry James , Lear Matthew , Pappo Alberto S. , Wang Zhaoming , Wilson Carmen L. , Cheng Yong , Meshinchi Soheil , Alexandrov Ludmil B. , Weiss Mitchell J. , Armstrong Gregory T. , Robison Leslie L. , Yasui Yutaka , Nichols Kim E. , Ellison David W. , Bangur Chaitanya , Mullighan Charles G. , Baker Suzanne J. , Dyer Michael A. , Miller Geralyn , Newman Scott , Rusch Michael , Daly Richard , Perry Keith , Downing James R. , Zhang Jinghui
Published: April 2023

Abstract
Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem—Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community—enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes.
Significance:
To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community.

This article is highlighted in the In This Issue feature, p. 995
Data from Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma
Authors: Zhang Qianfei , Ma Chi , Duan Yi , Heinrich Bernd , Rosato Umberto , Diggs Laurence P. , Ma Lichun , Roy Soumen , Fu Qiong , Brown Zachary J. , Wabitsch Simon , Thovarai Vishal , Fu Jianyang , Feng Dechun , Ruf Benjamin , Cui Linda L. , Subramanyam Varun , Frank Karen M. , Wang Sophie , Kleiner David E. , Ritz Thomas , Rupp Christian , Gao Bin , Longerich Thomas , Kroemer Alexander , Wang Xin Wei , Ruchirawat Mathuros , Korangy Firouzeh , Schnabl Bernd , Trinchieri Giorgio , Greten Tim F.
Published: April 2023

Abstract
Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer.
Significance:
MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.

See related commentary by Chagani and Kwong, p. 1014.

This article is highlighted in the In This Issue feature, p. 995
Data from Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma
Authors: Puca Francesca , Yu Fei , Bartolacci Caterina , Pettazzoni Piergiorgio , Carugo Alessandro , Huang-Hobbs Emmet , Liu Jintan , Zanca Ciro , Carbone Federica , Del Poggetto Edoardo , Gumin Joy , Dasgupta Pushan , Seth Sahil , Srinivasan Sanjana , Lang Frederick F. , Sulman Erik P. , Lorenzi Philip L. , Tan Lin , Shan Mengrou , Tolstyka Zachary P. , Kachman Maureen , Zhang Li , Gao Sisi , Deem Angela K. , Genovese Giannicola , Scaglioni Pier Paolo , Lyssiotis Costas A. , Viale Andrea , Draetta Giulio F.
Published: April 2023

Abstract
Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.
Significance:
MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.

This article is highlighted in the In This Issue feature, p. 2659