bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Association of Genetic Ancestry and Molecular Signatures with Cancer Survival Disparities: A Pan-Cancer Analysis
Authors: Lee Kara Keun , Rishishwar Lavanya , Ban Dongjo , Nagar Shashwat Deepali , Mariño-Ramírez Leonardo , McDonald John F. , Jordan I. King
Published: March 2024

Abstract
While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSCC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which, seven protein-coding genes [progestin and adipoQ receptor family member 6 (PAQR6), Lck-interacting transmembrane adaptor 1 (LIME1), Sin3A-associated protein 25 (SAP25), MAX dimerization protein 3 (MXD3), coiled-coil glutamate rich protein 2 (CCER2), refilin A (RFLNA), and cathepsin W (CTSW)] significantly interacted with GA and exacerbated observed survival disparities. These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.
Significance:
This large-cohort, multicancer study identifies four cancer types with cancer survival disparities and seven cancer-related genes that interact with genetic ancestry and contribute to disparities.
Data from Reorganization of the 3D Genome Pinpoints Noncoding Drivers of Primary Prostate Tumors
Authors: Hawley James R. , Zhou Stanley , Arlidge Christopher , Grillo Giacomo , Kron Ken J. , Hugh-White Rupert , van der Kwast Theodorus H. , Fraser Michael , Boutros Paul C. , Bristow Robert G. , Lupien Mathieu
Published: March 2024

Abstract
Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer.
Significance:
This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis.
Data from Plasticity in the Absence of NOTCH Uncovers a RUNX2-Dependent Pathway in Small Cell Lung Cancer
Authors: Hong Deli , Knelson Erik H. , Li Yixiang , Durmaz Yavuz T. , Gao Wenhua , Walton Emily , Vajdi Amir , Thai Tran , Sticco-Ivins Maura , Sabet Amin H. , Jones Kristen L. , Schinzel Anna C. , Bronson Rod T. , Nguyen Quang-De , Tolstorukov Michael Y. , Vivero Marina , Signoretti Sabina , Barbie David A. , Oser Matthew G.
Published: March 2024

Abstract
Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect SCLC tumorigenesis. In a CRISPR-based genetically engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch-mutant SCLCs still formed nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations.
Significance:
A genetically engineered mouse model of NOTCH-mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST–dependent pathway and innate immune signaling.
Data from Oncogenic circRNA C190 Promotes Non–Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway
Authors: Ishola Afeez Adekunle , Chien Chian-Shiu , Yang Yi-Ping , Chien Yueh , Yarmishyn Aliaksandr A. , Tsai Ping-Hsing , Chen Jerry Chieh-Yu , Hsu Po-Kuei , Luo Yung-Hung , Chen Yuh-Min , Liang Kung-Hou , Lan Yuan-Tzu , Huo Teh-Ia , Ma Hsin-I. , Chen Ming-Teh , Wang Mong-Lien , Chiou Shih-Hwa
Published: March 2024

Abstract
Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non–small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR–MAPK–ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.
Significance:
The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.
Data from Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma
Authors: Carrabotta Marianna , Laginestra Maria Antonella , Durante Giorgio , Mancarella Caterina , Landuzzi Lorena , Parra Alessandro , Ruzzi Francesca , Toracchio Lisa , De Feo Alessandra , Giusti Veronica , Pasello Michela , Righi Alberto , Lollini Pier-Luigi , Palmerini Emanuela , Donati Davide Maria , Manara Maria Cristina , Scotlandi Katia
Published: March 2024

Abstract
Capicua-double homeobox 4 (CIC-DUX4)–rearranged sarcomas (CDS) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. Patients are treated according to Ewing sarcoma protocols, but CDS-specific therapies are strongly needed. In this study, RNA sequencing was performed on patient samples to identify a selective signature that differentiates CDS from Ewing sarcoma and other fusion-driven sarcomas. This signature was used to validate the representativeness of newly generated CDS experimental models—patient-derived xenografts (PDX) and PDX-derived cell lines—and to identify specific therapeutic vulnerabilities. Annotation analysis of differentially expressed genes and molecular gene validation highlighted an HMGA2/IGF2BP/IGF2/IGF1R/AKT/mTOR axis that characterizes CDS and renders the tumors particularly sensitive to combined treatments with trabectedin and PI3K/mTOR inhibitors. Trabectedin inhibited IGF2BP/IGF2/IGF1R activity, but dual inhibition of the PI3K and mTOR pathways was required to completely dampen downstream signaling mediators. Proof-of-principle efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer.
Significance:
This study identifies altered HMGA2/IGF2BP/IGF2 signaling in CIC-DUX4 sarcomas and provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to specifically combat the disease.
Data from Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression
Authors: Park Soonbum , Rong Lijie , Owczarek Tomasz B. , Bernardo Matteo Di , Shoulson Rivka L. , Chua Chee-Wai , Kim Jaime Y. , Lankarani Amir , Chakrapani Prithi , Syed Talal , McKiernan James M. , Solit David B. , Shen Michael M. , Al-Ahmadie Hikmat A. , Abate-Shen Cory
Published: March 2024

Abstract
To study the progression of bladder cancer from non–muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease.
Significance:
Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.
Data from Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion
Authors: Byron Sara A. , Hendricks William P.D. , Nagulapally Abhinav B. , Kraveka Jacqueline M. , Ferguson William S. , Brown Valerie I. , Eslin Don E. , Mitchell Deanna , Cornelius Albert , Roberts William , Isakoff Michael S. , Oesterheld Javier E. , Wada Randal K. , Rawwas Jawhar , Neville Kathleen , Zage Peter E. , Harrod Virginia L. , Bergendahl Genevieve , VanSickle Elizabeth , Dykema Karl , Bond Jeffrey , Chou Hsien-Chao , Wei Jun S. , Wen Xinyu , Reardon Hue V. , Roos Alison , Nasser Sara , Izatt Tyler , Enriquez Daniel , Hegde Apurva M. , Cisneros Faith , Christofferson Austin , Turner Bryce , Szelinger Szabolcs , Keats Jonathan J. , Halperin Rebecca F. , Khan Javed , Saulnier Sholler Giselle L. , Trent Jeffrey M.
Published: March 2024

Abstract
Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment.
Significance:
Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
Data from A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer
Authors: Son Jieun , Jang Jaebong , Beyett Tyler S. , Eum Yoonji , Haikala Heidi M. , Verano Alyssa , Lin Mika , Hatcher John M. , Kwiatkowski Nicholas P. , Eser Pinar Ö. , Poitras Michael J. , Wang Stephen , Xu Man , Gokhale Prafulla C. , Cameron Michael D. , Eck Michael J. , Gray Nathanael S. , Jänne Pasi A.
Published: March 2024

Abstract
In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non–small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08–178–01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08–178–01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08–178–01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08–178–01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08–178–01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.
Significance:
This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.
Data from Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy
Authors: Wang Qiushi , Morris Rebecca J. , Bode Ann M. , Zhang Tianshun
Published: March 2024

Abstract
Because of profound effects observed in carcinogenesis, prostaglandins (PG), prostaglandin-endoperoxide synthases, and PG receptors are implicated in cancer development and progression. Understanding the molecular mechanisms of PG actions has potential clinical relevance for cancer prevention and therapy. This review focuses on the current status of PG signaling pathways in modulating cancer progression and aims to provide insights into the mechanistic actions of PGs and their receptors in influencing tumor progression. We also examine several small molecules identified as having anticancer activity that target prostaglandin receptors. The literature suggests that targeting PG pathways could provide opportunities for cancer prevention and therapy.
Data from Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids
Authors: Hsu Kuo-Shun , Adileh Mohammad , Martin Maria Laura , Makarov Vladimir , Chen Jiapeng , Wu Chao , Bodo Sahra , Klingler Stefan , Sauvé Charles-Etienne Gabriel , Szeglin Bryan C. , Smith J. Joshua , Fuks Zvi , Riaz Nadeem , Chan Timothy A. , Nishimura Makoto , Paty Philip B. , Kolesnick Richard
Published: March 2024

Abstract
Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination–mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.
Significance:
Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.
Data from CRISPR/Cas9-Induced DNA Damage Enriches for Mutations in a p53-Linked Interactome: Implications for CRISPR-Based Therapies
Authors: Jiang Long , Ingelshed Katrine , Shen Yunbing , Boddul Sanjaykumar V. , Iyer Vaishnavi Srinivasan , Kasza Zsolt , Sedimbi Saikiran , Lane David P. , Wermeling Fredrik
Published: March 2024

Abstract
Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR–p53 tumor suppressor interactome. Such enrichment could predispose to cancer development and thus pose a challenge for clinical CRISPR use. Transient p53 inhibition could suppress the enrichment of cells with these mutations. The level of DNA damage response induced by an sgRNA influenced the enrichment of p53-deficient cells and could be a relevant parameter in sgRNA design to limit cellular enrichment. Furthermore, a dataset of >800 human cancer cell lines identified additional factors influencing the enrichment of p53-mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR–p53 axis. Taken together, these data provide details about p53 biology in the context of CRISPR-induced DNA damage and identify strategies to enable safer CRISPR use.
Significance:
CRISPR-mediated DNA damage enriches for cells with escape mutations in a core CRISPR–p53 interactome, which can be suppressed by transient inhibition of p53.
Data from Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types
Authors: Sinha Neelam , Sinha Sanju , Valero Cristina , Schäffer Alejandro A. , Aldape Kenneth , Litchfield Kevin , Chan Timothy A. , Morris Luc G.T. , Ruppin Eytan
Published: March 2024

Abstract
The FDA has recently approved a high tumor mutational burden (TMB-high) biomarker, defined by ≥10 mutations/Mb, for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer types, and the mechanisms underlying this observation have remained unknown. The tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power), determining if it will be predictive of ICI response in a given cancer type. To systematically study this hypothesis, we inferred the levels of 31 immune-related factors characteristic of the TME of different cancer types in The Cancer Genome Atlas. Integration of this information with TMB and response data of 2,277 patients treated with anti-PD1 identified key immune factors that determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterized cancer types with high TMB power. A model based on these two immune factors strongly predicted TMB power in a given cancer type during cross-validation and testing (Spearman Rho = 0.76 and 1, respectively). Using this model, we predicted the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available. Our analysis indicates that TMB-high may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.
Significance:
This study uncovers immune-related factors that may modulate the relationship between high tumor mutational burden and ICI response, which can help prioritize cancer types for clinical trials.
Data from Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis
Authors: Casciello Francesco , Kelly Gregory M. , Ramarao-Milne Priya , Kamal Nabilah , Stewart Teneale A. , Mukhopadhyay Pamela , Kazakoff Stephen H. , Miranda Mariska , Kim Dorim , Davis Felicity M. , Hayward Nicholas K. , Vertino Paula M. , Waddell Nicola , Gannon Frank , Lee Jason S.
Published: March 2024

Abstract
G9a and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, yet the precise roles that these enzymes play cooperatively in cancer is unclear. We demonstrate here that frequent concurrent upregulation of both G9a and EZH2 occurs in several human tumors. These methyltransferases cooperatively repressed molecular pathways responsible for tumor cell death. In genetically distinct tumor subtypes, concomitant inhibition of G9a and EZH2 potently induced tumor cell death, highlighting the existence of tumor cell survival dependency at the epigenetic level. G9a and EZH2 synergistically repressed expression of genes involved in the induction of endoplasmic reticulum (ER) stress and the production of reactive oxygen species. IL24 was essential for the induction of tumor cell death and was identified as a common target of G9a and EZH2. Loss of function of G9a and EZH2 activated the IL24-ER stress axis and increased apoptosis in cancer cells while not affecting normal cells. These results indicate that G9a and EZH2 promotes the evasion of ER stress–mediated apoptosis by repressing IL24 transcription, therefore suggesting that their inhibition may represent a potential therapeutic strategy for solid cancers.
Significance:
These findings demonstrate a novel role for G9a and EZH2 histone methyltransferases in suppressing apoptosis, which can be targeted with small molecule inhibitors as a potential approach to improve solid cancer treatment.
Data from Tumor Expression Quantitative Trait Methylation Screening Reveals Distinct CpG Panels for Deconvolving Cancer Immune Signatures
Authors: Yu Xiaoqing , Cen Ling , Chen Y. Ann , Markowitz Joseph , Shaw Timothy I. , Tsai Kenneth Y. , Conejo-Garcia Jose R. , Wang Xuefeng
Published: March 2024

Abstract
DNA methylation signatures in tumors could serve as reliable biomarkers that are accessible in archival tissues for tracking the epigenetic dynamics shaped by both cancer cells and the tumor microenvironment. However, given the ultrahigh dimensionality and noncollapsible nature of the data, it remains challenging to screen all CpG sites to identify the most promising marker panels. In this article, we introduce the concept of tumor-based expression quantitative trait methylation (eQTM) for the prioritization and systematic mining of predictive biomarkers. In melanoma as a disease model, eQTM CpGs and genes represent new and efficient candidate targets to be investigated for both prognostic and immune status monitoring purposes. Three cis-eQTM CpGs (cg07786657, cg12446199, and cg00027570) were strongly associated with and can serve as surrogate biomarkers for the tumor immune cytolytic activity score (CYT). In addition, multiple eQTM genes could be further exploited for predicting immunoregulatory phenotypes. A targeted gene panel analysis identified one eQTM in TCF7 (cg25947408) as a novel candidate biomarker for uncoupling overall T-cell differentiation and exhaustion status in a tumor. The prognostic significance of this eQTM as an independent signature to CYT was validated by both The Cancer Genome Atlas and Moffitt melanoma cohort data. Overall, eQTMs represent a mechanistically distinct class of potential biomarkers that can be used to predict patient prognosis and immune status.
Significance:
This study provides a novel and promising approach to identify targeted epigenetic biomarkers in cancer and will spur further analysis in tumor immune phenotyping.
Data from Gain of Chromosome 1q Perturbs a Competitive Endogenous RNA Network to Promote Melanoma Metastasis
Authors: Xu Xiaonan , Wang Kaizhen , Vera Olga , Verma Akanksha , Jasani Neel , Bok Ilah , Elemento Olivier , Du Dongliang , Yu Xiaoqing , Karreth Florian A.
Published: March 2024

Abstract
Somatic copy-number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA), which sponge miRNAs to posttranscriptionally regulate gene expression in a protein coding–independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs.
Significance:
The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester tumor suppressor microRNAs underlies the oncogenic activity of chromosome 1q gains.
Data from The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis
Authors: Lacroix Marion , Beauchemin Hugues , Fraszczak Jennifer , Ross Julie , Shooshtarizadeh Peiman , Chen Riyan , Möröy Tarik
Published: March 2024

Abstract
The X-linked gene DDX3X encodes an RNA helicase that is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis, causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one Ddx3x allele is sufficient for fetal hematopoietic development in females and that the Ddx3y allele can compensate for the loss of Ddx3x in males. In adult mice, DDX3X deficiency altered hematopoietic progenitors, early lymphoid development, marginal zone and germinal center B cells, and lymphomagenesis in a sex-dependent manner. Loss of both Ddx3x alleles abrogated MYC-driven lymphomagenesis in females, whereas Ddx3x deletion in males did not affect the formation of B-cell lymphoma in both mouse models. Moreover, tumors that appeared in male mice lacking DDX3X showed upregulated expression of DDX3Y, indicating a critical requirement for DDX3 activity for lymphomagenesis. These data reveal sex-specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis.
Significance:
The sex-dependent effects of DDX3X deficiency in malignant transformation of B cells and the compensatory role of DDX3Y support inhibition of DDX3 as a treatment strategy for MYC-driven B-cell lymphoma.
Data from Mapping the Immune Landscape in Metastatic Melanoma Reveals Localized Cell–Cell Interactions That Predict Immunotherapy Response
Authors: Antoranz Asier , Van Herck Yannick , Bolognesi Maddalena M. , Lynch Seodhna M. , Rahman Arman , Gallagher William M. , Boecxstaens Veerle , Marine Jean-Christophe , Cattoretti Giorgio , van den Oord Joost J. , De Smet Frederik , Bechter Oliver , Bosisio Francesca M.
Published: March 2024

Abstract
While immune checkpoint–based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed IHC to spatially characterize the immune landscape of metastatic melanoma from responders and nonresponders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve toward an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1+ macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI.
Significance:
This study shows that spatial characterization can address the challenge of finding efficient biomarkers, revealing that localization of macrophages and T cells in melanoma predicts patient response to ICI.

See related commentary by Smalley and Smalley, p. 3198
Data from PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma
Authors: Yi Jiaqing , Kim BongWoo , Shi Xuanming , Zhan Xiaoming , Lu Q. Richard , Xuan Zhenyu , Wu Jiang
Published: March 2024

Abstract
Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones.
Significance:
The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.
Data from Sustained Oncogenic Signaling in the Cytostatic State Enables Targeting of Nonproliferating Persistent Cancer Cells
Authors: Kim Lisa M. , Kim Paul Y. , Gebreyohannes Yemarshet K. , Leung Cheuk T.
Published: March 2024

Abstract
Many advanced therapeutics possess cytostatic properties that suppress cancer cell growth without directly inducing death. Treatment-induced cytostatic cancer cells can persist and constitute a reservoir from which recurrent growth and resistant clones can develop. Current management approaches primarily comprise maintenance and monitoring because strategies for targeting nonproliferating cancer cells have been elusive. Here, we used targeted therapy paradigms and engineered cytostatic states to explore therapeutic opportunities for depleting treatment-mediated cytostatic cancer cells. Sustained oncogenic AKT signaling was common, while nonessential, in treatment-mediated cytostatic cancer cells harboring PI3K-pathway mutations, which are associated with cancer recurrence. Engineering oncogenic signals in quiescent mammary organotypic models showed that sustained, aberrant activation of AKT sensitized cytostatic epithelial cells to proteasome inhibition. Mechanistically, sustained AKT signaling altered cytostatic state homeostasis and promoted an oxidative and proteotoxic environment, which imposed an increased proteasome dependency for maintaining cell viability. Under cytostatic conditions, inhibition of the proteasome selectively induced apoptosis in the population with aberrant AKT activation compared with normal cells. Therapeutically exploiting this AKT-driven proteasome vulnerability was effective in depleting treatment-mediated cytostatic cancer cells independent of breast cancer subtype, epithelial origin, and cytostatic agent. Moreover, transient targeting during cytostatic treatment conditions was sufficient to reduce recurrent tumor growth in spheroid and mouse models. This work identified an AKT-driven proteasome-vulnerability that enables depletion of persistent cytostatic cancer cells harboring PTEN–PI3K pathway mutations, revealing a viable strategy for targeting nonproliferating persistent cancer cell populations before drug resistance emerges.
Significance:
This study finds that sustained oncogenic signaling in therapy-induced cytostatic cancer cells confers targetable vulnerabilities to deplete persistent cancer cell populations and reduce cancer recurrence.
Data from Ancient Human Endogenous Retroviruses Contribute to Genetic Evolution and Regulate Cancer Cell Type–Specific Gene Expression
Authors: Chen Mingyue , Jia Lei , Zheng Xiaofeng , Han Mingshu , Li Lin , Zhang Lei
Published: March 2024

Abstract
Human endogenous retroviruses (HERV), a type of transposable elements (TE), play crucial roles in human placental morphogenesis, immune response, and cancer progression. Emerging evidence suggests that TEs have been a rich source of regulatory elements in the human genome, but little is known about the global impact of HERVs on transcriptional networks in cancer. Using genome-wide approaches, we show that HERVs are composed primarily of three ancient superfamilies: ERVL-MaLR, ERVL, and ERV1. This analysis suggests that the integration of exonic, intronic, and intergenic HERVs, as well as human or Hominidae gene-specific HERVs, contributes to human genomic innovation. HERVs exonized in genes are located mainly in the 3′ untranslated region (UTR) or 3′ end and participate in basic biological processes. Active HERVs are located mainly in intronic and intergenic regions and tend to function as enhancers and contribute to cancer cell type–specific gene expression. More importantly, HERVs may also define chromatin topologically associating domain (TAD) and loop boundaries in a cell type–specific manner. Taken together, these findings reveal that ancient HERV elements are a source of diverse regulatory sequences, including 3′ UTRs, 5′ UTRs, promoters, and enhancers, and they contribute to genetic innovation and cancer cell type–specific gene expression, highlighting the previously underestimated importance of these elements.
Significance:
Genome-wide analyses show that human endogenous retroviruses mediate cancer cell type–specific gene expression, epigenetic modification, and 3D chromatin architecture, elucidating the relationship between HERVs and diverse cancers.
Data from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Authors: Distefano Rosario , Tomasello Luisa , Rampioni Vinciguerra Gian Luca , Gasparini Pierluigi , Xiang Yujia , Bagnoli Marina , Marceca Gioacchino P. , Fadda Paolo , Laganà Alessandro , Acunzo Mario , Ma Qin , Nigita Giovanni , Croce Carlo M.
Published: March 2024

Abstract
Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in >13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression.
Significance:
Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification.
Data from A Programmable In Vivo CRISPR Activation Model Elucidates the Oncogenic and Immunosuppressive Functions of MYC in Lung Adenocarcinoma
Authors: Thege Fredrik I. , Rupani Dhwani N. , Barathi Bhargavi Brahmendra , Manning Sara L. , Maitra Anirban , Rhim Andrew D. , Wörmann Sonja M.
Published: March 2024

Conventional genetically engineered mouse models (GEMM) are time-consuming, laborious, and offer limited spatiotemporal control. Here, we describe the development of a streamlined platform for in vivo gene activation using CRISPR activation (CRISPRa) technology. Unlike conventional GEMMs, this model system allows for flexible, sustained, and timed activation of one or more target genes using single or pooled lentiviral guides. Myc and Yap1 were used as model oncogenes to demonstrate gene activation in primary pancreatic organoid cultures in vitro and enhanced tumorigenic potential in Myc-activated organoids when transplanted orthotopically in vivo. Implementation of this model as an autochthonous lung cancer model showed that transduction-mediated activation of Myc led to accelerated tumor progression and significantly reduced overall survival relative to nontargeted tumor controls. Furthermore, Myc activation led to the acquisition of an immune suppressive, “cold” tumor microenvironment. Cross-species validation of these results using publicly available RNA/DNA-seq datasets linked MYC to a previously described immunosuppressive molecular subtype in patient tumors, thus identifying a patient cohort that may benefit from combined MYC- and immune-targeted therapies. Overall, this work demonstrates how CRISPRa can be used for rapid functional validation of putative oncogenes and may allow for the identification and evaluation of potential metastatic and oncogenic drivers through competitive screening.
Significance:
A streamlined platform for programmable CRISPR gene activation enables rapid evaluation and functional validation of putative oncogenes in vivo.
Data from Hypoxia-Reoxygenation Couples 3βHSD1 Enzyme and Cofactor Upregulation to Facilitate Androgen Biosynthesis and Hormone Therapy Resistance in Prostate Cancer
Authors: Qin Liang , Chung Yoon-Mi , Berk Michael , Naelitz Bryan , Zhu Ziqi , Klein Eric , Chakraborty Abhishek A. , Sharifi Nima
Published: March 2024

Abstract
Androgen deprivation therapy suppresses tumor androgen receptor (AR) signaling by depleting circulating testosterone and is a mainstay treatment for advanced prostate cancer. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. Here we investigated how changes in oxygenation affect androgen synthesis. In prostate cancer cells, chronic hypoxia coupled to reoxygenation resulted in efficient metabolism of androgen precursors to produce androgens and activate AR. Hypoxia induced 3βHSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenished necessary cofactors, suggesting that hypoxia and reoxygenation both facilitate potent androgen synthesis. The EGLN1/VHL/HIF2α pathway induced 3βHSD1 expression through direct binding of HIF2α to the 5′ regulatory region of HSD3B1 to promote transcription. Overexpression of HIF2α facilitated prostate cancer progression, which largely depended on 3βHSD1. Inhibition of HIF2α with the small-molecule PT2399 prevented prostate cancer cell proliferation. These results thus identify HIF2α as a regulator of androgen synthesis and potential therapeutic target in prostate cancer.
Significance:
Hypoxia followed by reoxygenation in prostate cancer drives androgen deprivation therapy resistance via increasing the rate-limiting enzyme and cofactors for androgen synthesis, revealing HIF2α as a therapeutic target to subvert resistance.
Data from Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer
Authors: Nandi Ajeya , Debnath Rahul , Nayak Anupma , To Tsun Ki Jerrick , Thacker Gatha , Reilly Megan , Gumber Sanjeev , Karagounis Ilias , Li Ning , Lengner Christopher J. , Haldar Malay , Welm Alana L. , Blanco Andres M. , Thomas Christoforos , Chakrabarti Rumela
Published: March 2024

Abstract
Resistance to radiotherapy is a major obstacle for effective cancer treatment. Both cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) and Notch signaling are implicated in radioresistance, but their potential interrelationship is unclear. Here, we report that irradiated samples obtained from luminal breast cancer patient tumors express higher levels of the Notch ligand Dll1 and have a greater number of αSMA- and FAP-expressing activated CAFs. Single cell transcriptomic profiles further revealed enrichment of an αSMA+ myofibroblastic subpopulation of CAF in Dll1+ tumors. In murine and human patient-derived xenograft models, Dll1+ tumor cells were more radioresistant than Dll1– tumor cells, and genetic and pharmacologic blocking of Dll1-mediated Notch signaling decreased the number of Dll1+ cancer stem cells (CSC) and CAFs and increased Dll1+ tumor cell radiosensitivity. Dll1+ cells recruited CAFs in an IL6-dependent fashion and promoted Wnt ligand secretion by Notch2/3-expressing CAFs, thereby driving Wnt/β-catenin–dependent increases in Dll1+ CSC function to promote metastasis. Treatment with the porcupine inhibitor LGK-974 that inhibits Wnt ligand secretion or pharmacologic blockade of IL6 or Dll1 suppressed CAF-dependent enhancement of Dll1+ CSC function and metastasis in radioresistant tumors. Together, these findings reveal an essential cross-talk between Dll1+ cancer cells and CAFs, which promotes metastasis and radioresistance, which could be therapeutically exploited to improve the outcome of patients with breast cancer.
Significance:
Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to β-catenin–driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.
Data from Benign SNPs in the Coding Region of TP53: Finding the Needles in a Haystack of Pathogenic Variants
Authors: Soussi Thierry
Published: March 2024

Abstract
With the recent explosion in high-throughput genotyping technology, the amount and quality of SNP data have increased exponentially, facilitating the discovery of multiple uncommon SNPs in the human population. To provide unified and centralized resources for the scientific community, several repositories have been developed that aggregate numerous population studies and serve widely as references to filter natural variants in genetic analyses. However, they are largely biased toward European populations. TP53 gene is the most frequently mutated gene in human cancer, and pathogenic germline TP53 variants are associated with several cancer susceptibility disorders such as Li–Fraumeni syndrome. For these reasons, it is essential that TP53 SNPs are rigorously evaluated to avoid misclassifications that could impair patient management. The recent discovery of numerous benign SNPs within the coding region of TP53 can be attributed to surveillance of both global repositories and population-specific databases, with the latter enabling the recognition of additional TP53 SNPs in Japanese, African, and Indian populations. This review summarizes the body of evidence behind the identification of 21 TP53 variants and the information defining them as bona fide SNPs. This illustrates the need to include populations of different ethnic origins in genetic studies and the substantial benefits that can be derived from the information.