bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System
Authors: Yachida Shinichi , Totoki Yasushi , Noë Michaël , Nakatani Yoichiro , Horie Masafumi , Kawasaki Kenta , Nakamura Hiromi , Saito-Adachi Mihoko , Suzuki Masami , Takai Erina , Hama Natsuko , Higuchi Ryota , Hirono Seiko , Shiba Satoshi , Kato Mamoru , Furukawa Eisaku , Arai Yasuhito , Rokutan Hirofumi , Hashimoto Taiki , Mitsunaga Shuichi , Kanda Mitsuro , Tanaka Hidenori , Takata So , Shimomura Ayaka , Oshima Minoru , Hackeng Wenzel M. , Okumura Tomoyuki , Okano Keiichi , Yamamoto Masakazu , Yamaue Hiroki , Morizane Chigusa , Arihiro Koji , Furukawa Toru , Sato Toshiro , Kiyono Tohru , Brosens Lodewijk A.A. , Wood Laura D. , Hruban Ralph H. , Shibata Tatsuhiro
Published: April 2023

Abstract
The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.
Significance:
GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic and epigenomic features.

This article is highlighted in the In This Issue feature, p. 587
Data from A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity
Authors: Abrego Jaime , Sanford-Crane Hannah , Oon Chet , Xiao Xu , Betts Courtney B. , Sun Duanchen , Nagarajan Shanthi , Diaz Luis , Sandborg Holly , Bhattacharyya Sohinee , Xia Zheng , Coussens Lisa M. , Tontonoz Peter , Sherman Mara H.
Published: April 2023

Abstract
Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near uniformly lethal. Although immune-modulatory therapies hold promise to meaningfully improve outcomes for patients with PDAC, the development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Here, we show that cancer cell–intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate–aspartate shuttle and promotes the transcriptional activity of nuclear receptor peroxisome proliferator–activated receptor delta (PPARδ), facilitated by direct fatty acid binding. Although GOT2 is dispensable for cancer cell proliferation in vivo, the GOT2–PPARδ axis promotes spatial restriction of both CD4+ and CD8+ T cells from the tumor microenvironment. Our results demonstrate a noncanonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response.
Significance:
Prior studies demonstrate the important moonlighting functions of metabolic enzymes in cancer. We find that the mitochondrial transaminase GOT2 binds directly to fatty acid ligands that regulate the nuclear receptor PPARδ, and this functional interaction critically regulates the immune microenvironment of pancreatic cancer to promote tumor progression.

See related commentary by Nwosu and di Magliano, p. 2237..

This article is highlighted in the In This Issue feature, p. 2221
Data from Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia
Authors: Galán-Díez Marta , Borot Florence , Ali Abdullah Mahmood , Zhao Junfei , Gil-Iturbe Eva , Shan Xiaochuan , Luo Na , Liu Yongfeng , Huang Xi-Ping , Bisikirska Brygida , Labella Rossella , Kurland Irwin , Roth Bryan L. , Quick Matthias , Mukherjee Siddhartha , Rabadán Raul , Carroll Martin , Raza Azra , Kousteni Stavroula
Published: April 2023

Abstract
Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1—the rate-limiting enzyme for kynurenine synthesis—thereby enabling AML progression. This leukemia–osteoblast cross-talk, conferred by the kynurenine–HTR1B–SAA–IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment.
Significance:
AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine–HTR1B–SAA–IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance.

This article is highlighted in the In This Issue feature, p. 873
Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon
Authors: Rousseau Benoit , Bieche Ivan , Pasmant Eric , Hamzaoui Nadim , Leulliot Nicolas , Michon Lucas , de Reynies Aurelien , Attignon Valerie , Foote Michael B. , Masliah-Planchon Julien , Svrcek Magali , Cohen Romain , Simmet Victor , Augereau Paule , Malka David , Hollebecque Antoine , Pouessel Damien , Gomez-Roca Carlos , Guimbaud Rosine , Bruyas Amandine , Guillet Marielle , Grob Jean-Jacques , Duluc Muriel , Cousin Sophie , de la Fouchardiere Christelle , Flechon Aude , Rolland Frederic , Hiret Sandrine , Saada-Bouzid Esma , Bouche Olivier , Andre Thierry , Pannier Diane , El Hajbi Farid , Oudard Stephane , Tournigand Christophe , Soria Jean-Charles , Champiat Stephane , Gerber Drew G. , Stephens Dennis , Lamendola-Essel Michelle F. , Maron Steven B. , Diplas Bill H. , Argiles Guillem , Krishnan Asha R. , Tabone-Eglinger Severine , Ferrari Anthony , Segal Neil H. , Cercek Andrea , Hoog-Labouret Natalie , Legrand Frederic , Simon Clotilde , Lamrani-Ghaouti Assia , Diaz Luis A. , Saintigny Pierre , Chevret Sylvie , Marabelle Aurelien
Published: April 2023

Abstract
Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.
Significance:
POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy.

See related video: https://vimeo.com/720727355

This article is highlighted in the In This Issue feature, p. 1397
Data from Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages
Authors: Wilson Taylor L. , Kim Hyunjin , Chou Ching-Heng , Langfitt Deanna , Mettelman Robert C. , Minervina Anastasia A. , Allen E. Kaitlynn , Métais Jean-Yves , Pogorelyy Mikhail V. , Riberdy Janice M. , Velasquez M. Paulina , Kottapalli Pratibha , Trivedi Sanchit , Olsen Scott R. , Lockey Timothy , Willis Catherine , Meagher Michael M. , Triplett Brandon M. , Talleur Aimee C. , Gottschalk Stephen , Crawford Jeremy Chase , Thomas Paul G.
Published: April 2023

Abstract
Current chimeric antigen receptor-modified (CAR) T-cell products are evaluated in bulk, without assessing functional heterogeneity. We therefore generated a comprehensive single-cell gene expression and T-cell receptor (TCR) sequencing data set using pre- and postinfusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B-cell acute lymphoblastic leukemia. We identified cytotoxic postinfusion cells with identical TCRs to a subset of preinfusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared with other preinfusion cells, corresponding to an unexpected surface phenotype (TIGIT+, CD62Llo, CD27−). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor TOX. Collectively, these results demonstrate diverse effector potentials within preinfusion CAR T-cell products, which can be exploited for therapeutic applications. Furthermore, we provide an integrative experimental and analytic framework for elucidating the mechanisms underlying effector development in CAR T-cell products.
Significance:
Utilizing clonal trajectories to define transcriptional potential, we find a unique signature of CAR T-cell effector precursors present in preinfusion cell products. Functional assessment of cells with this signature indicated early effector potential and resistance to exhaustion, consistent with postinfusion cellular patterns observed in patients.

This article is highlighted in the In This Issue feature, p. 2007
Data from Smarca4 Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung
Authors: Concepcion Carla P. , Ma Sai , LaFave Lindsay M. , Bhutkar Arjun , Liu Manyuan , DeAngelo Lydia P. , Kim Jonathan Y. , Del Priore Isabella , Schoenfeld Adam J. , Miller Manon , Kartha Vinay K. , Westcott Peter M.K. , Sánchez-Rivera Francisco J. , Meli Kevin , Gupta Manav , Bronson Roderick T. , Riely Gregory J. , Rekhtman Natasha , Rudin Charles M. , Kim Carla F. , Regev Aviv , Buenrostro Jason D. , Jacks Tyler
Published: April 2023

Abstract
SMARCA4/BRG1 encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of SMARCA4 mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of Smarca4 sensitizes club cell secretory protein–positive cells within the lung in a cell type–dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cell state. Mechanistically, we show that Smarca4 loss impairs the function of all three classes of SWI/SNF complexes, resulting in decreased chromatin accessibility at lung lineage motifs and ultimately accelerating tumor progression. Thus, we propose that the SWI/SNF complex via Smarca4 acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
Significance:
We demonstrate cell-type specificity in the tumor-suppressive functions of SMARCA4 in the lung, pointing toward a critical role of the cell-of-origin in driving SWI/SNF-mutant lung adenocarcinoma. We further show the direct effects of SMARCA4 loss on SWI/SNF function and chromatin regulation that cause aggressive malignancy during lung cancer evolution.

This article is highlighted in the In This Issue feature, p. 275
Data from NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron–Sulfur Cluster Proteins
Authors: Santana-Codina Naiara , del Rey Maria Quiles , Kapner Kevin S. , Zhang Huan , Gikandi Ajami , Malcolm Callum , Poupault Clara , Kuljanin Miljan , John Kristen M. , Biancur Douglas E. , Chen Brandon , Das Nupur K. , Lowder Kristen E. , Hennessey Connor J. , Huang Wesley , Yang Annan , Shah Yatrik M. , Nowak Jonathan A. , Aguirre Andrew J. , Mancias Joseph D.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor NCOA4, resulting in release of iron for cellular utilization. Using patient-derived and murine models of PDAC, we demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability, thereby promoting tumor progression. Quantitative proteomics reveals that ferritinophagy fuels iron–sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with the development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in patients with PDAC. Together, our data reveal that the maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.
Significance:
Autophagy and iron metabolism are metabolic dependencies in PDAC. However, targeted therapies for these pathways are lacking. We identify NCOA4-mediated selective autophagy of ferritin (“ferritinophagy”) as upregulated in PDAC. Ferritinophagy supports PDAC iron metabolism and thereby tumor progression and represents a new therapeutic target in PDAC.

See related commentary by Jain and Amaravadi, p. 2023.

See related article by Ravichandran et al., p. 2198.

This article is highlighted in the In This Issue feature, p. 2007
Data from The Genomics of Colorectal Cancer in Populations with African and European Ancestry
Authors: Myer Parvathi A. , Lee Jessica K. , Madison Russell W. , Pradhan Kith , Newberg Justin Y. , Isasi Carmen R. , Klempner Samuel J. , Frampton Garrett M. , Ross Jeffery S. , Venstrom Jeffrey M. , Schrock Alexa B. , Das Sudipto , Augenlicht Leonard , Verma Amit , Greally John M. , Raj Srilakshmi M. , Goel Sanjay , Ali Siraj M.
Published: April 2023

Abstract
Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability–high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer (<50 years), AFR and EUR had a similar frequency of MSI-H and tumor mutational burden–high (TMB-H) tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of the diverse U.S. population.
Significance:
KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC.

See related commentary by Eng and Holowatyj, p. 1187.

This article is highlighted in the In This Issue feature, p. 1171
Data from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Authors: Salmon Jessica M. , Todorovski Izabela , Stanley Kym L. , Bruedigam Claudia , Kearney Conor J. , Martelotto Luciano G. , Rossello Fernando , Semple Timothy , Arnau Gisela Mir , Zethoven Magnus , Bots Michael , Bjelosevic Stefan , Cluse Leonie A. , Fraser Peter J. , Litalien Veronique , Vidacs Eva , McArthur Kate , Matthews Antony Y. , Gressier Elise , de Weerd Nicole A. , Lichte Jens , Kelly Madison J. , Hogg Simon J. , Hertzog Paul J. , Kats Lev M. , Vervoort Stephin J. , De Carvalho Daniel D. , Scheu Stefanie , Bedoui Sammy , Kile Benjamin T. , Lane Steven W. , Perkins Andrew C. , Wei Andrew H. , Dominguez Pilar M. , Johnstone Ricky W.
Published: April 2023

Abstract
Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.
Significance:
We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition.

This article is highlighted in the In This Issue feature, p. 1397
Data from Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors
Authors: Muik Alexander , Garralda Elena , Altintas Isil , Gieseke Friederike , Geva Ravit , Ben-Ami Eytan , Maurice-Dror Corinne , Calvo Emiliano , LoRusso Patricia M. , Alonso Guzman , Rodriguez-Ruiz Maria E. , Schoedel Kristina B. , Blum Jordan M. , Sänger Bianca , Salcedo Theodora W. , Burm Saskia M. , Stanganello Eliana , Verzijl Dennis , Vascotto Fulvia , Sette Angelica , Quinkhardt Juliane , Plantinga Theo S. , Toker Aras , van den Brink Edward N. , Fereshteh Mark , Diken Mustafa , Satijn David , Kreiter Sebastian , Breij Esther C.W. , Bajaj Gaurav , Lagkadinou Eleni , Sasser Kate , Türeci Özlem , Forssmann Ulf , Ahmadi Tahamtan , Şahin Uğur , Jure-Kunkel Maria , Melero Ignacio
Published: April 2023

Abstract
Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell–mediated antitumor immunity. DuoBody-PD-L1×4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell–mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy.
Significance:
DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs.

See related commentary by Li et al., p. 1184.

This article is highlighted in the In This Issue feature, p. 1171
Data from Converting Tumoral PD-L1 into a 4-1BB Agonist for Safer and More Effective Cancer Immunotherapy
Authors: Li Zihai , Azar Joseph H. , Rubinstein Mark P.
Published: April 2023

Summary:
Dose-limiting toxicities are thought to temper the efficacy of single-agent 4-1BB agonists. To overcome this hurdle, in this issue of Cancer Discovery, Muik and colleagues report preclinical and clinical studies describing a first-in-class bispecific fusion protein targeting 4-1BB and PD-L1.

See related article by Muik et al., p. 1248 (9).
Data from IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment
Authors: Hu Bo , Yu Mincheng , Ma Xiaolu , Sun Jialei , Liu Chenglong , Wang Chunyan , Wu Suiyi , Fu Peiyao , Yang Zhen , He Yungang , Zhu Yuanyuan , Huang Cheng , Yang Xinrong , Shi Yinghong , Qiu Shuangjian , Sun Huichuan , Zhu Andrew X. , Zhou Jian , Xu Yang , Zhu Di , Fan Jia
Published: April 2023

Abstract
The overall response rate for anti–PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNα and anti–PD-1–based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immunocompetent orthotopic and spontaneous HCC models, IFNα therapy synergized with anti–PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+CD8+ T cells. Mechanistically, IFNα suppressed HIF1α signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR–FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFNα reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade–induced immune response. Our findings suggest that IFNα and anti–PD-1 cotreatment is an effective novel combination strategy for patients with HCC.
Significance:
Our study supports a role of tumor glucose metabolism in IFNα-mediated antitumor immunity in HCC, and tumor-infiltrating CD27+CD8+ T cells may be a promising biomarker for stratifying patients for anti–PD-1 therapy.

See related commentary by Kao et al., p. 1615.

This article is highlighted in the In This Issue feature, p. 1599
Data from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients
Authors: Crisafulli Giovanni , Sartore-Bianchi Andrea , Lazzari Luca , Pietrantonio Filippo , Amatu Alessio , Macagno Marco , Barault Ludovic , Cassingena Andrea , Bartolini Alice , Luraghi Paolo , Mauri Gianluca , Battuello Paolo , Personeni Nicola , Zampino Maria Giulia , Pessei Valeria , Vitiello Pietro Paolo , Tosi Federica , Idotta Laura , Morano Federica , Valtorta Emanuele , Bonoldi Emanuela , Germano Giovanni , Di Nicolantonio Federica , Marsoni Silvia , Siena Salvatore , Bardelli Alberto
Published: April 2023

Abstract
The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment.
Significance:
MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments.

See related commentary by Willis and Overman, p. 1612.

This article is highlighted in the In This Issue feature, p. 1599
Data from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
Authors: Chang Chewei Anderson , Jen Jayu , Jiang Shaowen , Sayad Azin , Mer Arvind Singh , Brown Kevin R. , Nixon Allison M.L. , Dhabaria Avantika , Tang Kwan Ho , Venet David , Sotiriou Christos , Deng Jiehui , Wong Kwok-kin , Adams Sylvia , Meyn Peter , Heguy Adriana , Skok Jane A. , Tsirigos Aristotelis , Ueberheide Beatrix , Moffat Jason , Singh Abhyudai , Haibe-Kains Benjamin , Khodadadi-Jamayran Alireza , Neel Benjamin G.
Published: April 2023

Abstract
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. “Drug-tolerant persisters” (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor–dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
Significance:
DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (“pre-DTPs”) that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities.

This article is highlighted in the In This Issue feature, p. 873
Data from Improving the Affordability of Anticancer Medicines Demands Evidence-Based Policy Solutions
Authors: Franzen Nora , Romagnoli Giorgia , Ziegler Andreas , Retèl Valesca P. , Offerman Theo J.S. , van Harten Wim H.
Published: April 2023

Abstract
The high cost of many new anticancer medicines significantly impedes breakthrough discoveries from reaching patients. A commonly heard refrain is that high prices are necessary to compensate for the high costs of research and development (R&D). Yet, there are promising policy proposals aimed at improving affordability without compromising innovation. In seeking new policy solutions, we argue for a shift away from entrenched opinion toward an evidence-based discourse that is grounded in experiments and real-world pilot studies. We offer a novel perspective and practical recommendations on how empirical evidence could and should be gathered to inform evidence-based policy interventions that lead to sustainable medicine prices in oncology.

See related article by Franzen et al. (Cancer Res Commun 2022;2:39–47).
Data from SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk
Authors: Lukinović Valentina , Hausmann Simone , Roth Gael S. , Oyeniran Clement , Ahmad Tanveer , Tsao Ning , Brickner Joshua R. , Casanova Alexandre G. , Chuffart Florent , Benitez Ana Morales , Vayr Jessica , Rodell Rebecca , Tardif Marianne , Jansen Pascal W.T.C. , Couté Yohann , Vermeulen Michiel , Hainaut Pierre , Mazur Pawel K. , Mosammaparast Nima , Reynoird Nicolas
Published: April 2023

Abstract
Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy.
Significance:
SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy.

This article is highlighted in the In This Issue feature, p. 2007
Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C
Authors: Weiss Andreas , Lorthiois Edwige , Barys Louise , Beyer Kim S. , Bomio-Confaglia Claudio , Burks Heather , Chen Xueying , Cui Xiaoming , de Kanter Ruben , Dharmarajan Lekshmi , Fedele Carmine , Gerspacher Marc , Guthy Daniel Alexander , Head Victoria , Jaeger Ashley , Núñez Eloísa Jiménez , Kearns Jeffrey D. , Leblanc Catherine , Maira Sauveur-Michel , Murphy Jason , Oakman Helen , Ostermann Nils , Ottl Johannes , Rigollier Pascal , Roman Danielle , Schnell Christian , Sedrani Richard , Shimizu Toshio , Stringer Rowan , Vaupel Andrea , Voshol Hans , Wessels Peter , Widmer Toni , Wilcken Rainer , Xu Kun , Zecri Frederic , Farago Anna F. , Cotesta Simona , Brachmann Saskia M.
Published: April 2023

Abstract
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors.
Significance:
JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155.

See related video: https://vimeo.com/720726054

This article is highlighted in the In This Issue feature, p. 1397
Data from Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse
Authors: Gambacorta Valentina , Beretta Stefano , Ciccimarra Martina , Zito Laura , Giannetti Kety , Andrisani Angela , Gnani Daniela , Zanotti Lucia , Oliveira Giacomo , Carrabba Matteo Giovanni , Cittaro Davide , Merelli Ivan , Ciceri Fabio , Di Micco Raffaella , Vago Luca
Published: April 2023

Abstract
Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by nongenomic loss of HLA class II expression in leukemia cells. By integrative analysis of gene expression, DNA methylation, and chromatin accessibility in paired diagnosis/relapse primary samples and in the respective patient-derived xenografts (PDX), we identify the polycomb repressive complex 2 (PRC2) as a key epigenetic driver of this immune escape modality. We report that loss of expression of HLA class II molecules is accompanied by a PRC2-dependent reduction in chromatin accessibility. Pharmacologic inhibition of PRC2 subunits rescues HLA class II expression in AML relapses in vitro and in vivo, with consequent recovery of leukemia recognition by CD4+ T cells. Our results uncover a novel link between epigenetics and leukemia immune escape, which may rapidly translate into innovative strategies to cure or prevent AML posttransplantation relapse.
Significance:
Loss of HLA class II expression represents a frequent mechanism of leukemia posttransplantation relapse. Here we identify PRC2 as the main epigenetic driver of this immune escape modality and show that its chemical inhibition can reinstate a proficient graft-versus-leukemia effect, providing an innovative rationale for personalized epigenetic immunotherapies.

See related commentary by Köhler and Zeiser, p. 1410.

This article is highlighted in the In This Issue feature, p. 1397
Data from Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts
Authors: Ellegast Jana M. , Alexe Gabriela , Hamze Amanda , Lin Shan , Uckelmann Hannah J. , Rauch Philipp J. , Pimkin Maxim , Ross Linda S. , Dharia Neekesh V. , Robichaud Amanda L. , Conway Amy Saur , Khalid Delan , Perry Jennifer A. , Wunderlich Mark , Benajiba Lina , Pikman Yana , Nabet Behnam , Gray Nathanael S. , Orkin Stuart H. , Stegmaier Kimberly
Published: April 2023

Abstract
Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1β/TNFα signaling via NFκB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.
Significance:
This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death.

See related commentary by Puissant and Medyouf, p. 1617.

This article is highlighted in the In This Issue feature, p. 1599
Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Authors: Langille Ellen , Al-Zahrani Khalid N. , Ma Zhibo , Liang Minggao , Uuskula-Reimand Liis , Espin Roderic , Teng Katie , Malik Ahmad , Bergholtz Helga , Ghamrasni Samah El , Afiuni-Zadeh Somaieh , Tsai Ricky , Alvi Sana , Elia Andrew , Lü YiQing , Oh Robin H. , Kozma Katelyn J. , Trcka Daniel , Narimatsu Masahiro , Liu Jeff C. , Nguyen Thomas , Barutcu Seda , Loganathan Sampath K. , Bremner Rod , Bader Gary D. , Egan Sean E. , Cescon David W. , Sørlie Therese , Wrana Jeffrey L. , Jackson Hartland W. , Wilson Michael D. , Witkiewicz Agnieszka K. , Knudsen Erik S. , Pujana Miguel Angel , Wahl Geoffrey M. , Schramek Daniel
Published: April 2023

Abstract
Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology.
Significance:
Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis.

This article is highlighted in the In This Issue feature, p. 2711
Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Authors: Newell Felicity , Johansson Peter A. , Wilmott James S. , Nones Katia , Lakis Vanessa , Pritchard Antonia L. , Lo Serigne N. , Rawson Robert V. , Kazakoff Stephen H. , Colebatch Andrew J. , Koufariotis Lambros T. , Ferguson Peter M. , Wood Scott , Leonard Conrad , Law Matthew H. , Brooks Kelly M. , Broit Natasa , Palmer Jane M. , Couts Kasey L. , Vergara Ismael A. , Long Georgina V. , Barbour Andrew P. , Nieweg Omgo E. , Shivalingam Brindha , Robinson William A. , Stretch Jonathan R. , Spillane Andrew J. , Saw Robyn P.M. , Shannon Kerwin F. , Thompson John F. , Mann Graham J. , Pearson John V. , Scolyer Richard A. , Waddell Nicola , Hayward Nicholas K.
Published: April 2023

Abstract
Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes.
Significance:
This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma.

This article is highlighted in the In This Issue feature, p. 2711
Data from Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition
Authors: Jain Vaibhav , Harper Sandra L. , Versace Amanda M. , Fingerman Dylan , Brown Gregory Schuyler , Bhardwaj Monika , Crissey Mary Ann S. , Goldman Aaron R. , Ruthel Gordon , Liu Qin , Zivkovic Aleksandra , Stark Holgar , Herlyn Meenhard , Gimotty Phyllis A. , Speicher David W. , Amaravadi Ravi K.
Published: April 2023

Abstract
Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted.
Significance:
We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers.

This article is highlighted in the In This Issue feature, p. 247
Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia
Authors: Liu Yiman , Li Qinglan , Alikarami Fatemeh , Barrett Declan R. , Mahdavi Leila , Li Hangpeng , Tang Sylvia , Khan Tanweer A. , Michino Mayako , Hill Connor , Song Lele , Yang Lu , Li Yuanyuan , Pokharel Sheela Pangeni , Stamford Andrew W. , Liverton Nigel , Renzetti Louis M. , Taylor Simon , Watt Gillian F. , Ladduwahetty Tammy , Kargman Stacia , Meinke Peter T. , Foley Michael A. , Shi Junwei , Li Haitao , Carroll Martin , Chen Chun-Wei , Gardini Alessandro , Maillard Ivan , Huggins David J. , Bernt Kathrin M. , Wan Liling
Published: April 2023

Abstract
The chromatin reader eleven–nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9–mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line– and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach.
Significance:
AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation.

This article is highlighted in the In This Issue feature, p. 2483