bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cell of Origin Influences Pancreatic Cancer Subtype
Authors: Flowers Brittany M. , Xu Hang , Mulligan Abigail S. , Hanson Kathryn J. , Seoane Jose A. , Vogel Hannes , Curtis Christina , Wood Laura D. , Attardi Laura D.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell–derived and acinar cell–derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution.
Significance:
Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.

This article is highlighted in the In This Issue feature, p. 521
Data from Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma
Authors: Muthalagu Nathiya , Monteverde Tiziana , Raffo-Iraolagoitia Ximena , Wiesheu Robert , Whyte Declan , Hedley Ann , Laing Sarah , Kruspig Björn , Upstill-Goddard Rosanna , Shaw Robin , Neidler Sarah , Rink Curtis , Karim Saadia A. , Gyuraszova Katarina , Nixon Colin , Clark William , Biankin Andrew V. , Carlin Leo M. , Coffelt Seth B. , Sansom Owen J. , Morton Jennifer P. , Murphy Daniel J.
Published: April 2023

Abstract
MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC–MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival.
Significance:
We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC.

This article is highlighted in the In This Issue feature, p. 747
Data from Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy
Authors: Nowicki Theodore S. , Farrell Colin , Morselli Marco , Rubbi Liudmilla , Campbell Katie M. , Macabali Mignonette H. , Berent-Maoz Beata , Comin-Anduix Begoña , Pellegrini Matteo , Ribas Antoni
Published: April 2023

Abstract
Transgenic T-cell receptor (TCR) adoptive cell therapies recognizing tumor antigens are associated with robust initial response rates, but frequent disease relapse. This usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR, generated using murine stem cell virus (MSCV) γ-retroviral vectors. Analysis of clinical transgenic adoptive cell therapy products in vivo revealed that despite strong persistence of the transgenic TCR DNA sequence over time, its expression was profoundly decreased over time at the RNA and protein levels. Patients with the greatest degrees of expression suppression displayed significant increases in DNA methylation over time within the MSCV promoter region, as well as progressive increases in DNA methylation within the entire MSCV vector over time. These increases in vector methylation occurred independently of its integration site within the host genomes. These results have significant implications for the design of future viral vector gene–engineered adoptive cell transfer therapies.
Significance:
Cellular immunotherapies' reliance on retroviral vectors encoding foreign genetic material can be vulnerable to progressive acquisition of DNA methylation and subsequent epigenetic suppression of the transgenic product in TCR adoptive cell therapy. This must be considered in the design of future generations of cellular immunotherapies for cancer.

This article is highlighted in the In This Issue feature, p. 1611
Data from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
Authors: Hobbs G. Aaron , Baker Nicole M. , Miermont Anne M. , Thurman Ryan D. , Pierobon Mariaelena , Tran Timothy H. , Anderson Andrew O. , Waters Andrew M. , Diehl J. Nathaniel , Papke Bjoern , Hodge Richard G. , Klomp Jennifer E. , Goodwin Craig M. , DeLiberty Jonathan M. , Wang Junning , Ng Raymond W.S. , Gautam Prson , Bryant Kirsten L. , Esposito Dominic , Campbell Sharon L. , Petricoin Emanuel F. , Simanshu Dhirendra K. , Aguirre Andrew J. , Wolpin Brian M. , Wennerberg Krister , Rudloff Udo , Cox Adrienne D. , Der Channing J.
Published: April 2023

Abstract
Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy.
Significance:
We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.

See related commentary by Falcomatà et al., p. 23.

This article is highlighted in the In This Issue feature, p. 1
Data from Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment
Authors: Chen Peiwen , Hsu Wen-Hao , Chang Andrew , Tan Zhi , Lan Zhengdao , Zhou Ashley , Spring Denise J. , Lang Frederick F. , Wang Y. Alan , DePinho Ronald A.
Published: April 2023

Abstract
Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK–BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease.
Significance:
Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infiltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and/or OLFML3 may represent novel therapeutic targets for GBM.

This article is highlighted in the In This Issue feature, p. 327
Data from Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2
Authors: Alicea Gretchen M. , Rebecca Vito W. , Goldman Aaron R. , Fane Mitchell E. , Douglass Stephen M. , Behera Reeti , Webster Marie R. , Kugel Curtis H. , Ecker Brett L. , Caino M. Cecilia , Kossenkov Andrew V. , Tang Hsin-Yao , Frederick Dennie T. , Flaherty Keith T. , Xu Xiaowei , Liu Qin , Gabrilovich Dmitry I. , Herlyn Meenhard , Blair Ian A. , Schug Zachary T. , Speicher David W. , Weeraratna Ashani T.
Published: April 2023

Abstract
Older patients with melanoma (>50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals.
Significance:
These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance.

See related commentary by Montal and White, p. 1255.

This article is highlighted in the In This Issue feature, p. 1241
Data from Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease
Authors: Catenacci Daniel V.T. , Moya Stephanie , Lomnicki Samantha , Chase Leah M. , Peterson Bryan F. , Reizine Natalie , Alpert Lindsay , Setia Namrata , Xiao Shu-Yuan , Hart John , Siddiqui Uzma D. , Hogarth D. Kyle , Eng Oliver S. , Turaga Kiran , Roggin Kevin , Posner Mitchell C. , Chang Paul , Narula Sunil , Rampurwala Murtuza , Ji Yuan , Karrison Theodore , Liao Chih-Yi , Polite Blase N. , Kindler Hedy L.
Published: April 2023

Abstract
The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study.
Significance:
This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.

This article is highlighted in the In This Issue feature, p. 211
Data from Harnessing CAR T-cell Insights to Develop Treatments for Hyperinflammatory Responses in Patients with COVID-19
Authors: Agarwal Sangya , June Carl H.
Published: April 2023

AbstractSummary:
Cytokine release and macrophage activation contribute to immunopathology after SARS-CoV-2 infection. We discuss approaches to decrease the morbidity and mortality in patients with COVID-19 by repurposing existing drugs previously developed for cancer therapy.
Data from Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Authors: Sakuma Stephen , Raices Marcela , Borlido Joana , Guglielmi Valeria , Zhu Ethan Y.S. , D'Angelo Maximiliano A.
Published: April 2023

Abstract
Nuclear pore complexes (NPC) are the central mediators of nucleocytoplasmic transport. Increasing evidence shows that many cancer cells have increased numbers of NPCs and become addicted to the nuclear transport machinery. How reducing NPC numbers affects the physiology of normal and cancer cells and whether it could be exploited for cancer therapies has not been investigated. We report that inhibition of NPC formation, a process mostly restricted to proliferating cells, causes selective cancer cell death, prevents tumor growth, and induces tumor regression. Although cancer cells die in response to NPC assembly inhibition, normal cells undergo a reversible cell-cycle arrest that allows them to survive. Mechanistically, reducing NPC numbers results in multiple alterations contributing to cancer cell death, including abnormalities in nuclear transport, catastrophic alterations in gene expression, and the selective accumulation of DNA damage. Our findings uncover the NPC formation process as a novel targetable pathway in cancer cells.
Significance:
Reducing NPC numbers in cancer cells induces death, prevents tumor growth, and results in tumor regression. Conversely, normal cells undergo a reversible cell-cycle arrest in response to inhibition of NPC assembly. These findings expose the potential of targeting NPC formation in cancer.

This article is highlighted in the In This Issue feature, p. 1
Data from Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Authors: Diab Adi , Tannir Nizar M. , Bentebibel Salah-Eddine , Hwu Patrick , Papadimitrakopoulou Vassiliki , Haymaker Cara , Kluger Harriet M. , Gettinger Scott N. , Sznol Mario , Tykodi Scott S. , Curti Brendan D. , Tagliaferri Mary A. , Zalevsky Jonathan , Hannah Alison L. , Hoch Ute , Aung Sandra , Fanton Christie , Rizwan Ahsan , Iacucci Ernesto , Liao Yijie , Bernatchez Chantale , Hurwitz Michael E. , Cho Daniel C.
Published: April 2023

Abstract
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status.
Significance:
These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

See related commentary by Rouanne et al., p. 1097.

This article is highlighted in the In This Issue feature, p. 1079
Data from Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective In Vivo without Systemic Immune Activation
Authors: Kamata-Sakurai Mika , Narita Yoshinori , Hori Yuji , Nemoto Takayuki , Uchikawa Ryo , Honda Masaki , Hironiwa Naoka , Taniguchi Kenji , Shida-Kawazoe Meiri , Metsugi Shoichi , Miyazaki Taro , Wada Naoko A. , Ohte Yuki , Shimizu Shun , Mikami Hirofumi , Tachibana Tatsuhiko , Ono Natsuki , Adachi Kenji , Sakiyama Tetsushi , Matsushita Tomochika , Kadono Shojiro , Komatsu Shun-ichiro , Sakamoto Akihisa , Horikawa Sayuri , Hirako Ayano , Hamada Koki , Naoi Sotaro , Savory Nasa , Satoh Yasuko , Sato Motohiko , Noguchi Yuki , Shinozuka Junko , Kuroi Haruka , Ito Ami , Wakabayashi Tetsuya , Kamimura Masaki , Isomura Fumihisa , Tomii Yasushi , Sawada Noriaki , Kato Atsuhiko , Ueda Otoya , Nakanishi Yoshito , Endo Mika , Jishage Kou-ichi , Kawabe Yoshiki , Kitazawa Takehisa , Igawa Tomoyuki
Published: April 2023

Abstract
Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor-selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad antitumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy.
Significance:
Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression.

See related commentary by Keenan and Fong, p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from Deep Learning to Estimate RECIST in Patients with NSCLC Treated with PD-1 Blockade
Authors: Arbour Kathryn C. , Luu Anh Tuan , Luo Jia , Rizvi Hira , Plodkowski Andrew J. , Sakhi Mustafa , Huang Kevin B. , Digumarthy Subba R. , Ginsberg Michelle S. , Girshman Jeffrey , Kris Mark G. , Riely Gregory J. , Yala Adam , Gainor Justin F. , Barzilay Regina , Hellmann Matthew D.
Published: April 2023

Abstract
Real-world evidence (RWE), conclusions derived from analysis of patients not treated in clinical trials, is increasingly recognized as an opportunity for discovery, to reduce disparities, and to contribute to regulatory approval. Maximal value of RWE may be facilitated through machine-learning techniques to integrate and interrogate large and otherwise underutilized datasets. In cancer research, an ongoing challenge for RWE is the lack of reliable, reproducible, scalable assessment of treatment-specific outcomes. We hypothesized a deep-learning model could be trained to use radiology text reports to estimate gold-standard RECIST-defined outcomes. Using text reports from patients with non–small cell lung cancer treated with PD-1 blockade in a training cohort and two test cohorts, we developed a deep-learning model to accurately estimate best overall response and progression-free survival. Our model may be a tool to determine outcomes at scale, enabling analyses of large clinical databases.
Significance:
We developed and validated a deep-learning model trained on radiology text reports to estimate gold-standard objective response categories used in clinical trial assessments. This tool may facilitate analysis of large real-world oncology datasets using objective outcome metrics determined more reliably and at greater scale than currently possible.

This article is highlighted in the In This Issue feature, p. 1
Data from Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer
Authors: Sceneay Jaclyn , Goreczny Gregory J. , Wilson Kristin , Morrow Sara , DeCristo Molly J. , Ubellacker Jessalyn M. , Qin Yuanbo , Laszewski Tyler , Stover Daniel G. , Barrera Victor , Hutchinson John N. , Freedman Rachel A. , Mittendorf Elizabeth A. , McAllister Sandra S.
Published: April 2023

Abstract
Immune checkpoint blockade (ICB) therapy, which targets T cell–inhibitory receptors, has revolutionized cancer treatment. Among the breast cancer subtypes, evaluation of ICB has been of greatest interest in triple-negative breast cancer (TNBC) due to its immunogenicity, as evidenced by the presence of tumor-infiltrating lymphocytes and elevated PD-L1 expression relative to other subtypes. TNBC incidence is equally distributed across the age spectrum, affecting 10% to 15% of women in all age groups. Here we report that increased immune dysfunction with age limits ICB efficacy in aged TNBC-bearing mice. The tumor microenvironment in both aged mice and patients with TNBC shows decreased IFN signaling and antigen presentation, suggesting failed innate immune activation with age. Triggering innate immune priming with a STING agonist restored response to ICB in aged mice. Our data implicate age-related immune dysfunction as a mechanism of ICB resistance in mice and suggest potential prognostic utility of assessing IFN-related genes in patients with TNBC receiving ICB therapy.
Significance:
These data demonstrate for the first time that age determines the T cell–inflamed phenotype in TNBC and affects response to ICB in mice. Evaluating IFN-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an IFN pathway activator with ICB may be required.

This article is highlighted in the In This Issue feature, p. 1143
Data from Aggressive PDACs Show Hypomethylation of Repetitive Elements and the Execution of an Intrinsic IFN Program Linked to a Ductal Cell of Origin
Authors: Espinet Elisa , Gu Zuguang , Imbusch Charles D. , Giese Nathalia A. , Büscher Magdalena , Safavi Mariam , Weisenburger Silke , Klein Corinna , Vogel Vanessa , Falcone Mattia , Insua-Rodríguez Jacob , Reitberger Manuel , Thiel Vera , Kossi Steffi O. , Muckenhuber Alexander , Sarai Karnjit , Lee Alex Y.L. , Backx Elyne , Zarei Soheila , Gaida Matthias M. , Rodríguez-Paredes Manuel , Donato Elisa , Yen Hsi-Yu , Eils Roland , Schlesner Matthias , Pfarr Nicole , Hackert Thilo , Plass Christoph , Brors Benedikt , Steiger Katja , Weichenhan Dieter , Arda H. Efsun , Rooman Ilse , Kopp Janel L. , Strobel Oliver , Weichert Wilko , Sprick Martin R. , Trumpp Andreas
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylationlow tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylationlow/IFNsignhigh and Methylationhigh/IFNsignlow PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived KrasG12D/Trp53−/− mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylationlow/IFNsignhigh subtype potentially targetable by agents blocking intrinsic IFN signaling.
Significance:
The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity.

This article is highlighted in the In This Issue feature, p. 521
Data from A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1
Authors: Loizou Evangelia , Banito Ana , Livshits Geulah , Ho Yu-Jui , Koche Richard P. , Sánchez-Rivera Francisco J. , Mayle Allison , Chen Chi-Chao , Kinalis Savvas , Bagger Frederik O. , Kastenhuber Edward R. , Durham Benjamin H. , Lowe Scott W.
Published: April 2023

Abstract
Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer.
Significance:
Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.

This article is highlighted in the In This Issue feature, p. 813
Data from Lineage Reversion Drives WNT Independence in Intestinal Cancer
Authors: Han Teng , Goswami Sukanya , Hu Yang , Tang Fanying , Zafra Maria Paz , Murphy Charles , Cao Zhen , Poirier John T. , Khurana Ekta , Elemento Olivier , Hechtman Jaclyn F. , Ganesh Karuna , Yaeger Rona , Dow Lukas E.
Published: April 2023

Abstract
The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer–associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.
Significance:
Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells.

This article is highlighted in the In This Issue feature, p. 1426
Data from The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG
Authors: Ye Haobin , Minhajuddin Mohammad , Krug Anna , Pei Shanshan , Chou Chih-Hsing , Culp-Hill Rachel , Ponder Jessica , De Bloois Erik , Schniedewind Björn , Amaya Maria L. , Inguva Anagha , Stevens Brett M. , Pollyea Daniel A. , Christians Uwe , Grimes H. Leighton , D'Alessandro Angelo , Jordan Craig T.
Published: April 2023

Abstract
Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid–mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge.
Significance:
The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia.

This article is highlighted in the In This Issue feature, p. 211
Data from The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis
Authors: Hong Xin , Roh Whijae , Sullivan Ryan J. , Wong Keith H.K. , Wittner Ben S. , Guo Hongshan , Dubash Taronish D. , Sade-Feldman Moshe , Wesley Benjamin , Horwitz Elad , Boland Genevieve M. , Marvin Dieuwke L. , Bonesteel Todd , Lu Chenyue , Aguet François , Burr Risa , Freeman Samuel S. , Parida Laxmi , Calhoun Katherine , Jewett Michelle K. , Nieman Linda T. , Hacohen Nir , Näär Anders M. , Ting David T. , Toner Mehmet , Stott Shannon L. , Getz Gad , Maheswaran Shyamala , Haber Daniel A.
Published: April 2023

Abstract
Circulating tumor cells (CTC) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastasis. We show that single CTCs from patients with melanoma coordinately upregulate lipogenesis and iron homeostasis pathways. These are correlated with both intrinsic and acquired resistance to BRAF inhibitors across clonal cultures of BRAF-mutant CTCs. The lipogenesis regulator SREBP2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby conferring resistance to inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic antioxidants ferrostatin-1 and vitamin E. In a prospective melanoma cohort, presence of CTCs with high lipogenic and iron metabolic RNA signatures is correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBP2-driven iron homeostatic pathways contribute to cancer progression, drug resistance, and metastasis.
Significance:
Through single-cell analysis of primary and cultured melanoma CTCs, we have uncovered intrinsic cancer cell heterogeneity within lipogenic and iron homeostatic pathways that modulates resistance to BRAF inhibitors and to ferroptosis inducers. Activation of these pathways within CTCs is correlated with adverse clinical outcome, pointing to therapeutic opportunities.

This article is highlighted in the In This Issue feature, p. 521
Data from Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis
Authors: Halbritter Florian , Farlik Matthias , Schwentner Raphaela , Jug Gunhild , Fortelny Nikolaus , Schnöller Thomas , Pisa Hanja , Schuster Linda C. , Reinprecht Andrea , Czech Thomas , Gojo Johannes , Holter Wolfgang , Minkov Milen , Bauer Wolfgang M. , Simonitsch-Klupp Ingrid , Bock Christoph , Hutter Caroline
Published: April 2023

Abstract
Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions.
Significance:
This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy.

See related commentary by Gruber et al., p. 1343.

This article is highlighted in the In This Issue feature, p. 1325
Data from Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study
Authors: Rivera Donna R. , Peters Solange , Panagiotou Orestis A. , Shah Dimpy P. , Kuderer Nicole M. , Hsu Chih-Yuan , Rubinstein Samuel M. , Lee Brendan J. , Choueiri Toni K. , de Lima Lopes Gilberto , Grivas Petros , Painter Corrie A. , Rini Brian I. , Thompson Michael A. , Arcobello Jonathan , Bakouny Ziad , Doroshow Deborah B. , Egan Pamela C. , Farmakiotis Dimitrios , Fecher Leslie A. , Friese Christopher R. , Galsky Matthew D. , Goel Sanjay , Gupta Shilpa , Halfdanarson Thorvardur R. , Halmos Balazs , Hawley Jessica E. , Khaki Ali Raza , Lemmon Christopher A. , Mishra Sanjay , Olszewski Adam J. , Pennell Nathan A. , Puc Matthew M. , Revankar Sanjay G. , Schapira Lidia , Schmidt Andrew , Schwartz Gary K. , Shah Sumit A. , Wu Julie T. , Xie Zhuoer , Yeh Albert C. , Zhu Huili , Shyr Yu , Lyman Gary H. , Warner Jeremy L.
Published: April 2023

Abstract
Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials.
Significance:
Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access.

This article is highlighted in the In This Issue feature, p. 1426
Data from Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia
Authors: Bhatnagar Bhavana , Kohlschmidt Jessica , Mrózek Krzysztof , Zhao Qiuhong , Fisher James L. , Nicolet Deedra , Walker Christopher J. , Mims Alice S. , Oakes Christopher , Giacopelli Brian , Orwick Shelley , Boateng Isaiah , Blachly James S. , Maharry Sophia E. , Carroll Andrew J. , Powell Bayard L. , Kolitz Jonathan E. , Stone Richard M. , Byrd John C. , Paskett Electra D. , de la Chapelle Albert , Garzon Ramiro , Eisfeld Ann-Kathrin
Published: April 2023

Abstract
Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients <60 years, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival. Gene mutation profiles showed fewer NPM1 and more IDH2 mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by IDH2 mutations and FLT3-ITD, but, in contrast to White patients, was not improved by NPM1 mutations.
Significance:
We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed.

See related commentary by Vyas, p. 540.

This article is highlighted in the In This Issue feature, p. 521
Data from Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
Authors: Kansara Maya , Thomson Kristian , Pang Puiyi , Dutour Aurelie , Mirabello Lisa , Acher Francine , Pin Jean-Philippe , Demicco Elizabeth G. , Yan Juming , Teng Michele W.L. , Smyth Mark J. , Thomas David M.
Published: April 2023

Abstract
The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4−/− gene–targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/− mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis.
Significance:
Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.

See related commentary by Jones, p. 1484.

This article is highlighted in the In This Issue feature, p. 1469
Data from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents
Authors: Lossos Chen , Liu Yunpeng , Kolb Kellie E. , Christie Amanda L. , Van Scoyk Alexandria , Prakadan Sanjay M. , Shigemori Kay , Stevenson Kristen E. , Morrow Sara , Plana Olivia D. , Fraser Cameron , Jones Kristen L. , Liu Huiyun , Pallasch Christian P. , Modiste Rebecca , Nguyen Quang-De , Craig Jeffrey W. , Morgan Elizabeth A. , Vega Francisco , Aster Jon C. , Sarosiek Kristopher A. , Shalek Alex K. , Hemann Michael T. , Weinstock David M.
Published: April 2023

Abstract
The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a “super-phagocytic” subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance.
Significance:
mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress–dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types.

See related commentary by Duval and De Palma, p. 834.

This article is highlighted in the In This Issue feature, p. 813
Data from First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study
Authors: Khot Amit , Brajanovski Natalie , Cameron Donald P. , Hein Nadine , Maclachlan Kylee H. , Sanij Elaine , Lim John , Soong John , Link Emma , Blombery Piers , Thompson Ella R. , Fellowes Andrew , Sheppard Karen E. , McArthur Grant A. , Pearson Richard B. , Hannan Ross D. , Poortinga Gretchen , Harrison Simon J.
Published: April 2023

Abstract
RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.
Significance:
CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.

This article is highlighted in the In This Issue feature, p. 983