bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors
Authors: Morris Erick J. , Jha Sharda , Restaino Clifford R. , Dayananth Priya , Zhu Hugh , Cooper Alan , Carr Donna , Deng Yongi , Jin Weihong , Black Stuart , Long Brian , Liu Jenny , DiNunzio Edward , Windsor William , Zhang Rumin , Zhao Shuxia , Angagaw Minilik H. , Pinheiro Elaine M. , Desai Jagdish , Xiao Li , Shipps Gerald , Hruza Alan , Wang James , Kelly Joe , Paliwal Sunil , Gao Xiaolei , Babu Boga Sobhana , Zhu Liang , Daublain Pierre , Zhang Ling , Lutterbach Bart A. , Pelletier Marc R. , Philippar Ulrike , Siliphaivanh Phieng , Witter David , Kirschmeier Paul , Bishop W. Robert , Hicklin Daniel , Gilliland D. Gary , Jayaraman Lata , Zawel Leigh , Fawell Stephen , Samatar Ahmed A.
Published: March 2024

Abstract
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor–resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.

Significance: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742–50. ©2013 AACR.

See related commentary by Nissan et al., p. 719

This article is highlighted in the In This Issue feature, p. 705
Data from BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells
Authors: Valls Ester , Lobry Camille , Geng Huimin , Wang Ling , Cardenas Mariano , Rivas Martín , Cerchietti Leandro , Oh Philmo , Yang Shao Ning , Oswald Erin , Graham Camille W. , Jiang Yanwen , Hatzi Katerina , Agirre Xabier , Perkey Eric , Li Zhuoning , Tam Wayne , Bhatt Kamala , Leonard John P. , Zweidler-McKay Patrick A. , Maillard Ivan , Elemento Olivier , Ci Weimin , Aifantis Iannis , Melnick Ari
Published: March 2024

Abstract
Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2.

Significance: We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506–21. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 443
Data from Identification of a DNA Damage–Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers
Authors: Chen Jing , Crutchley John , Zhang Dadong , Owzar Kouros , Kastan Michael B.
Published: March 2024

Abstract
Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor TP53, and controls DNA damage–induced cellular senescence. In brief, ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA. RPL26, in turn, is required for the recruitment of the serine/arginine-rich splicing factor SRSF7 to p53 pre-mRNA and generation of alternatively spliced p53β RNA. Disruption of this pathway via selective knockout of p53β by CRISPR/Cas9 or downregulation of pathway constituents significantly reduces IR-induced senescence markers, and cells lacking p53β expression fail to transcriptionally repress negative regulators of cellular senescence and aging.

Significance: We identified a new component of the DDR pathway that regulates alternative splicing of messenger RNAs, including human TP53 mRNA. Modulation of this regulatory pathway affects DNA-damage induction of cellular senescence markers. Cancer Discov; 7(7); 766–81. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 653
Data from Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia
Authors: Teachey David T. , Lacey Simon F. , Shaw Pamela A. , Melenhorst J. Joseph , Maude Shannon L. , Frey Noelle , Pequignot Edward , Gonzalez Vanessa E. , Chen Fang , Finklestein Jeffrey , Barrett David M. , Weiss Scott L. , Fitzgerald Julie C. , Berg Robert A. , Aplenc Richard , Callahan Colleen , Rheingold Susan R. , Zheng Zhaohui , Rose-John Stefan , White Jason C. , Nazimuddin Farzana , Wertheim Gerald , Levine Bruce L. , June Carl H. , Porter David L. , Grupp Stephan A.
Published: March 2024

Abstract
Chimeric antigen receptor (CAR)–modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.

Significance: CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664–79. ©2016 AACR.

See related commentary by Rouce and Heslop, p. 579.

This article is highlighted in the In This Issue feature, p. 561
Data from The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
Authors: Pushalkar Smruti , Hundeyin Mautin , Daley Donnele , Zambirinis Constantinos P. , Kurz Emma , Mishra Ankita , Mohan Navyatha , Aykut Berk , Usyk Mykhaylo , Torres Luisana E. , Werba Gregor , Zhang Kevin , Guo Yuqi , Li Qianhao , Akkad Neha , Lall Sarah , Wadowski Benjamin , Gutierrez Johana , Kochen Rossi Juan Andres , Herzog Jeremy W. , Diskin Brian , Torres-Hernandez Alejandro , Leinwand Josh , Wang Wei , Taunk Pardeep S. , Savadkar Shivraj , Janal Malvin , Saxena Anjana , Li Xin , Cohen Deirdre , Sartor R. Balfour , Saxena Deepak , Miller George
Published: March 2024

Abstract
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.

Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR.

See related commentary by Riquelme et al., p. 386.

This article is highlighted in the In This Issue feature, p. 371
Data from Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia
Authors: Berrien-Elliott Melissa M. , Cashen Amanda F. , Cubitt Celia C. , Neal Carly C. , Wong Pamela , Wagner Julia A. , Foster Mark , Schappe Timothy , Desai Sweta , McClain Ethan , Becker-Hapak Michelle , Foltz Jennifer A. , Cooper Matthew L. , Jaeger Natalia , Srivatsan Sridhar Nonavinkere , Gao Feng , Romee Rizwan , Abboud Camille N. , Uy Geoffrey L. , Westervelt Peter , Jacoby Meagan A. , Pusic Iskra , Stockerl-Goldstein Keith E. , Schroeder Mark A. , DiPersio John , Fehniger Todd A.
Published: March 2024

Abstract
Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell–treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK–cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics.
Significance:
Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK–cell therapy. These findings identify multiple avenues for optimizing ML NK–cell immunotherapy for cancer and define mechanisms important for ML NK–cell function.

This article is highlighted in the In This Issue feature, p. 1775
Data from Lower Airway Dysbiosis Affects Lung Cancer Progression
Authors: Tsay Jun-Chieh J. , Wu Benjamin G. , Sulaiman Imran , Gershner Katherine , Schluger Rosemary , Li Yonghua , Yie Ting-An , Meyn Peter , Olsen Evan , Perez Luisannay , Franca Brendan , Carpenito Joseph , Iizumi Tadasu , El-Ashmawy Mariam , Badri Michelle , Morton James T. , Shen Nan , He Linchen , Michaud Gaetane , Rafeq Samaan , Bessich Jamie L. , Smith Robert L. , Sauthoff Harald , Felner Kevin , Pillai Ray , Zavitsanou Anastasia-Maria , Koralov Sergei B. , Mezzano Valeria , Loomis Cynthia A. , Moreira Andre L. , Moore William , Tsirigos Aristotelis , Heguy Adriana , Rom William N. , Sterman Daniel H. , Pass Harvey I. , Clemente Jose C. , Li Huilin , Bonneau Richard , Wong Kwok-Kin , Papagiannakopoulos Thales , Segal Leopoldo N.
Published: March 2024

Abstract
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers.
Significance:
Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.

See related commentary by Zitvogel and Kroemer, p. 224.

This article is highlighted in the In This Issue feature, p. 211
Data from Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers
Authors: Klotz Remi , Thomas Amal , Teng Teng , Han Sung Min , Iriondo Oihana , Li Lin , Restrepo-Vassalli Sara , Wang Alan , Izadian Negeen , MacKay Matthew , Moon Byoung-San , Liu Kevin J. , Ganesan Sathish Kumar , Lee Grace , Kang Diane S. , Walmsley Charlotte S. , Pinto Christopher , Press Michael F. , Lu Wange , Lu Janice , Juric Dejan , Bardia Aditya , Hicks James , Salhia Bodour , Attenello Frank , Smith Andrew D. , Yu Min
Published: March 2024

Abstract
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis.
Significance:
Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.

This article is highlighted in the In This Issue feature, p. 1
Data from Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment
Authors: Dey Prasenjit , Li Jun , Zhang Jianhua , Chaurasiya Surendra , Strom Anders , Wang Huamin , Liao Wen-Ting , Cavallaro Frederick , Denz Parker , Bernard Vincent , Yen Er-Yen , Genovese Giannicola , Gulhati Pat , Liu Jielin , Chakravarti Deepavali , Deng Pingna , Zhang Tingxin , Carbone Federica , Chang Qing , Ying Haoqiang , Shang Xiaoying , Spring Denise J. , Ghosh Bidyut , Putluri Nagireddy , Maitra Anirban , Wang Y. Alan , DePinho Ronald A.
Published: March 2024

Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ–IL4rα and IL2rγ–IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ–IL4rα and IL2rγ–IL13rα1 receptors signal primarily via JAK1–STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC.
Significance:
Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell–intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.
Data from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer
Authors: Smyth Lillian M. , Piha-Paul Sarina A. , Won Helen H. , Schram Alison M. , Saura Cristina , Loi Sherene , Lu Janice , Shapiro Geoffrey I. , Juric Dejan , Mayer Ingrid A. , Arteaga Carlos L. , de la Fuente Macarena I. , Brufksy Adam M. , Spanggaard Iben , Mau-Sørensen Morten , Arnedos Monica , Moreno Victor , Boni Valentina , Sohn Joohyuk , Schwartzberg Lee S. , Gonzàlez-Farré Xavier , Cervantes Andrés , Bidard François-Clement , Gorelick Alexander N. , Lanman Richard B. , Nagy Rebecca J. , Ulaner Gary A. , Chandarlapaty Sarat , Jhaveri Komal , Gavrila Elena I. , Zimel Catherine , Selcuklu S. Duygu , Melcer Myra , Samoila Aliaksandra , Cai Yanyan , Scaltriti Maurizio , Mann Grace , Xu Feng , Eli Lisa D. , Dujka Melanie , Lalani Alshad S. , Bryce Richard , Baselga José , Taylor Barry S. , Solit David B. , Meric-Bernstam Funda , Hyman David M.
Published: March 2024

Abstract
HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.
Significance:
HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.

This article is highlighted in the In This Issue feature, p. 161
Data from Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
Authors: Dong Zhen , Zhang Guoxin , Qu Meng , Gimple Ryan C. , Wu Qiulian , Qiu Zhixin , Prager Briana C. , Wang Xiuxing , Kim Leo J.Y. , Morton Andrew R. , Dixit Deobrat , Zhou Wenchao , Huang Haidong , Li Bin , Zhu Zhe , Bao Shideng , Mack Stephen C. , Chavez Lukas , Kay Steve A. , Rich Jeremy N.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 1469
Data from Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment
Authors: Chen Xufeng , Glytsou Christina , Zhou Hua , Narang Sonali , Reyna Denis E. , Lopez Andrea , Sakellaropoulos Theodore , Gong Yixiao , Kloetgen Andreas , Yap Yoon Sing , Wang Eric , Gavathiotis Evripidis , Tsirigos Aristotelis , Tibes Raoul , Aifantis Iannis
Published: March 2024

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

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

This article is highlighted in the In This Issue feature, p. 813
Data from Discovery of Candidate DNA Methylation Cancer Driver Genes
Authors: Pan Heng , Renaud Loïc , Chaligne Ronan , Bloehdorn Johannes , Tausch Eugen , Mertens Daniel , Fink Anna Maria , Fischer Kirsten , Zhang Chao , Betel Doron , Gnirke Andreas , Imielinski Marcin , Moreaux Jérôme , Hallek Michael , Meissner Alexander , Stilgenbauer Stephan , Wu Catherine J. , Elemento Olivier , Landau Dan A.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 2113
Data from Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma
Authors: Puca Francesca , Yu Fei , Bartolacci Caterina , Pettazzoni Piergiorgio , Carugo Alessandro , Huang-Hobbs Emmet , Liu Jintan , Zanca Ciro , Carbone Federica , Del Poggetto Edoardo , Gumin Joy , Dasgupta Pushan , Seth Sahil , Srinivasan Sanjana , Lang Frederick F. , Sulman Erik P. , Lorenzi Philip L. , Tan Lin , Shan Mengrou , Tolstyka Zachary P. , Kachman Maureen , Zhang Li , Gao Sisi , Deem Angela K. , Genovese Giannicola , Scaglioni Pier Paolo , Lyssiotis Costas A. , Viale Andrea , Draetta Giulio F.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 2659
Data from MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
Authors: Zhang Yong , Yang Qifan , Zeng Xiangyu , Wang Manxiang , Dong Shuang , Yang Bin , Tu Xinyi , Wei Ting , Xie Wenzhuan , Zhang Chao , Guo Qiang , Kloeber Jake A. , Cao Yueyu , Guo Guijie , Zhou Qin , Zhao Fei , Huang Jinzhou , Liu Li , Zhang Kai , Wang Mingwei , Yin Ping , Luo Kuntian , Deng Min , Kim Wootae , Hou Jing , Shi Yu , Zhu Qian , Chen Lifeng , Hu Sheng , Yue Junqiu , Pi Guoliang , Lou Zhenkun
Published: March 2024

Abstract
Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET.
Significance:
We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification.

This article is highlighted in the In This Issue feature, p. 2659
Data from Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway
Authors: Li Pupu , Chen Xinfeng , Qin Guohui , Yue Dongli , Zhang Zhen , Ping Yu , Wang Dan , Zhao Xuan , Song Mengjia , Zhao Qitai , Li Jieyao , Liu Shasha , Wang Dong , Zhang Chaoqi , Lian Jingyao , Cao Ling , Li Feng , Huang Lan , Wang Liping , Yang Li , Huang Jianmin , Li Hong , Zhang Bin , Zhang Yi
Published: March 2024

Abstract
Maelstrom (MAEL) is a novel cancer/testis-associated gene, which is not only expressed in the male testicular germ cells among human normal tissues, but is also aberrantly expressed in various cancer tissues. In our study, MAEL was characterized as a tumor-promoting gene and was significantly associated with esophageal squamous cell carcinoma (ESCC) recurrence and unfavorable prognosis. Kaplan–Meier analysis showed that patients with high MAEL expression had a shorter survival time. Functional experiments showed that MAEL promoted tumor cell growth and inhibited cell apoptosis. These results prompted us to investigate the factors affecting the tumorigenicity of MAEL. Further experimentation demonstrated that MAEL enhanced the expression of phosphorylated Akt1, with subsequent phosphorylation of nuclear factor kappa B (NF-κB) subunit RelA in tumor cells, and chemoattracted myeloid-derived suppressor cells (MDSCs) by upregulating interleukin-8 (IL8) to accelerate tumor progression in the tumor microenvironment. We also found that TGFβ secreted by MDSCs could upregulate MAEL by inducing Smad2/Smad3 phosphorylation. In summary, this study revealed a mechanism by which MAEL could upregulate IL8 through Akt1/RelA to direct MDSCs homing into the tumor, suggesting that MAEL could be an attractive therapeutic target and a prognostic marker against ESCC. Cancer Immunol Res; 6(10); 1246–59. ©2018 AACR.
Data from Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants
Authors: Krenciute Giedre , Prinzing Brooke L. , Yi Zhongzhen , Wu Meng-Fen , Liu Hao , Dotti Gianpietro , Balyasnikova Irina V. , Gottschalk Stephen
Published: March 2024

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens.

Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss variants highlights the need to target multiple tumor antigens. Cancer Immunol Res; 5(7); 571–81. ©2017 AACR.
Data from Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models
Authors: Hekim Can , Ilander Mette , Yan Jun , Michaud Erin , Smykla Richard , Vähä-Koskela Markus , Savola Paula , Tähtinen Siri , Saikko Leena , Hemminki Akseli , Kovanen Panu E. , Porkka Kimmo , Lee Francis Y.F. , Mustjoki Satu
Published: March 2024

Abstract
Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8+ T cells in PB, together with a higher amount of tumor-infiltrating CD8+ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4+ and CD8+ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157–69. ©2017 AACR.
Data from The Different T-cell Receptor Repertoires in Breast Cancer Tumors, Draining Lymph Nodes, and Adjacent Tissues
Authors: Wang Ting , Wang Changxi , Wu Jinghua , He Chenyang , Zhang Wei , Liu Jiayun , Zhang Ruifang , Lv Yonggang , Li Yongping , Zeng Xiaojing , Cao Hongzhi , Zhang Xiuqing , Xu Xun , Huang Chen , Wang Ling , Liu Xiao
Published: March 2024

Abstract
T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148–56. ©2016 AACR.
Data from MicroRNA MIR21 and T Cells in Colorectal Cancer
Authors: Mima Kosuke , Nishihara Reiko , Nowak Jonathan A. , Kim Sun A. , Song Mingyang , Inamura Kentaro , Sukawa Yasutaka , Masuda Atsuhiro , Yang Juhong , Dou Ruoxu , Nosho Katsuhiko , Baba Hideo , Giovannucci Edward L. , Bowden Michaela , Loda Massimo , Giannakis Marios , Bass Adam J. , Dranoff Glenn , Freeman Gordon J. , Chan Andrew T. , Fuchs Charles S. , Qian Zhi Rong , Ogino Shuji
Published: March 2024

Abstract
The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell–mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T-cell density in colorectal carcinoma tissue. Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay. Densities of CD3+, CD8+, CD45RO (PTPRC)+, and FOXP3+ cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features, including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted the two-sided α level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3+ and CD45RO+ cells (Ptrend < 0.0005). The multivariate odds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3+ or CD45RO+ cells was 0.44 [95% confidence interval (CI), 0.28 to 0.68] or 0.41 (95% CI, 0.26–0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell–mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer. Cancer Immunol Res; 4(1); 33–40. ©2015 AACR.
Data from Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells
Authors: Zhang Rong , Liu Tian-Yi , Senju Satoru , Haruta Miwa , Hirosawa Narumi , Suzuki Motoharu , Tatsumi Minako , Ueda Norihiro , Maki Hiroyuki , Nakatsuka Ryusuke , Matsuoka Yoshikazu , Sasaki Yutaka , Tsuzuki Shinobu , Nakanishi Hayao , Araki Ryoko , Abe Masumi , Akatsuka Yoshiki , Sakamoto Yasushi , Sonoda Yoshiaki , Nishimura Yasuharu , Kuzushima Kiyotaka , Uemura Yasushi
Published: March 2024

Abstract
The use of dendritic cells (DC) to prime tumor-associated antigen-specific T-cell responses provides a promising approach to cancer immunotherapy. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can differentiate into functional DCs, thus providing an unlimited source of DCs. However, the previously established methods of generating practical volumes of DCs from pluripotent stem cells (PSC) require a large number of PSCs at the start of the differentiation culture. In this study, we generated mouse proliferating myeloid cells (pMC) as a source of antigen-presenting cells (APC) using lentivirus-mediated transduction of the c-Myc gene into mouse PSC-derived myeloid cells. The pMCs could propagate almost indefinitely in a cytokine-dependent manner, while retaining their potential to differentiate into functional APCs. After treatment with IL4 plus GM-CSF, the pMCs showed impaired proliferation and differentiated into immature DC-like cells (pMC-DC) expressing low levels of major histocompatibility complex (MHC)-I, MHC-II, CD40, CD80, and CD86. In addition, exposure to maturation stimuli induced the production of TNFα and IL12p70, and enhanced the expression of MHC-II, CD40, and CD86, which is thus suggestive of typical DC maturation. Similar to bone marrow–derived DCs, they stimulated a primary mixed lymphocyte reaction. Furthermore, the in vivo transfer of pMC-DCs pulsed with H-2Kb-restricted OVA257-264 peptide primed OVA-specific cytotoxic T cells and elicited protection in mice against challenge with OVA-expressing melanoma. Overall, myeloid cells exhibiting cytokine-dependent proliferation and DC-like differentiation may be used to address issues associated with the preparation of DCs. Cancer Immunol Res; 3(6); 668–77. ©2015 AACR.
Data from Tasquinimod Modulates Suppressive Myeloid Cells and Enhances Cancer Immunotherapies in Murine Models
Authors: Shen Li , Sundstedt Anette , Ciesielski Michael , Miles Kiersten Marie , Celander Mona , Adelaiye Remi , Orillion Ashley , Ciamporcero Eric , Ramakrishnan Swathi , Ellis Leigh , Fenstermaker Robert , Abrams Scott I. , Eriksson Helena , Leanderson Tomas , Olsson Anders , Pili Roberto
Published: March 2024

Abstract
A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies. Cancer Immunol Res; 3(2); 136–48. ©2014 AACR.