bluuebunny/crossref_metadata_2025 huggingface dataset:
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 2023

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 The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations
Authors: Ulicna Livia , Kimmey Samuel C. , Weber Christopher M. , Allard Grace M. , Wang Aihui , Bui Nam Q. , Bendall Sean C. , Crabtree Gerald R. , Bean Gregory R. , Van Rechem Capucine
Published: March 2023

Abstract
Subunits from the chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) are mutated, deleted, or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancerous alterations will provide insight into developing new targeted therapies. Here we examined whether mSWI/SNF mutations increase cellular sensitivity to specific drugs. Taking advantage of the DepMap studies, we demonstrate that cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are sensitive to translation pathway inhibitors. Furthermore, mSWI/SNF subunits were present in the cytoplasm and interacted with the translation initiation machinery, and short-term inhibition and depletion of specific subunits decreased global translation, implicating a direct role for these factors in translation. Depletion of specific mSWI/SNF subunits also increased sensitivity to mTOR-PI3K inhibitors. In patient-derived breast cancer samples, mSWI/SNF subunits expression in both the nucleus and the cytoplasm was substantially altered. In conclusion, an unexpected cytoplasmic role for mSWI/SNF complexes in translation suggests potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in their subunits.
Significance:
This work establishes direct functions for mSWI/SNF in translation and demonstrates that alterations in mSWI/SNF confer a therapeutic vulnerability to translation pathway inhibitors in cancer cells.
Data from A Protumorigenic mDia2–MIRO1 Axis Controls Mitochondrial Positioning and Function in Cancer-Associated Fibroblasts
Authors: Cangkrama Michael , Liu Huan , Whipman James , Zubair Maria , Matsushita Mai , Di Filippo Michela , Kopf Manfred , Innocenti Metello , Werner Sabine
Published: March 2023

Abstract
Cancer-associated fibroblasts (CAF) are key regulators of tumorigenesis. Further insights into the tumor-promoting mechanisms of action of CAFs could help improve cancer diagnosis and treatment. Here we show that the formin mDia2 regulates the positioning and function of mitochondria in dermal fibroblasts, thereby promoting a protumorigenic CAF phenotype. Mechanistically, mDia2 stabilized the mitochondrial trafficking protein MIRO1. Loss of mDia2 or MIRO1 in fibroblasts or CAFs reduced the presence of mitochondria and ATP levels near the plasma membrane and at CAF-tumor cell contact sites, caused metabolic alterations characteristic of mitochondrial dysfunction, and suppressed the secretion of protumorigenic proteins. In mouse models of squamous carcinogenesis, genetic or pharmacologic inhibition of mDia2, MIRO1, or their common upstream regulator activin A inhibited tumor formation. Consistently, co-upregulation of mDia2 and MIRO1 in the stroma of various human cancers negatively correlated with survival. This work unveils a key role of mitochondria in the protumorigenic CAF phenotype and identifies an activin A–mDia2–MIRO1 signaling axis in CAFs with diagnostic and therapeutic potential.
Significance:
Inhibition of mDia2/MIRO1-mediated mitochondrial positioning in CAFs induces mitochondrial dysfunction and suppresses tumor growth, revealing a promising therapeutic strategy to target tumor–stroma cross-talk.
Data from Leveraging Therapy-Specific Polygenic Risk Scores to Predict Restrictive Lung Defects in Childhood Cancer Survivors
Authors: Im Cindy , Yuan Yan , Austin Eric D. , Stokes Dennis C. , Krasin Matthew J. , Davidoff Andrew M. , Sapkota Yadav , Wang Zhaoming , Ness Kirsten K. , Wilson Carmen L. , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Mulrooney Daniel A. , Yasui Yutaka
Published: March 2023

Abstract
Therapy-related pulmonary complications are among the leading causes of morbidity among long-term survivors of childhood cancer. Restrictive ventilatory defects (RVD) are prevalent, with risks increasing after exposures to chest radiotherapy and radiomimetic chemotherapies. Using whole-genome sequencing data from 1,728 childhood cancer survivors in the St. Jude Lifetime Cohort Study, we developed and validated a composite RVD risk prediction model that integrates clinical profiles and polygenic risk scores (PRS), including both published lung phenotype PRSs and a novel survivor-specific pharmaco/radiogenomic PRS (surPRS) for RVD risk reflecting gene-by-treatment (GxT) interaction effects. Overall, this new therapy-specific polygenic risk prediction model showed multiple indicators for superior discriminatory accuracy in an independent data set. The surPRS was significantly associated with RVD risk in both training (OR = 1.60, P = 3.7 × 10−10) and validation (OR = 1.44, P = 8.5 × 10−4) data sets. The composite model featuring the surPRS showed the best discriminatory accuracy (AUC = 0.81; 95% CI, 0.76–0.87), a significant improvement (P = 9.0 × 10−3) over clinical risk scores only (AUC = 0.78; 95% CI: 0.72–0.83). The odds of RVD in survivors in the highest quintile of composite model-predicted risk was ∼20-fold higher than those with median predicted risk or less (OR = 20.01, P = 2.2 × 10−16), exceeding the comparable estimate considering nongenetic risk factors only (OR = 9.20, P = 7.4 × 10−11). Inclusion of genetic predictors also selectively improved risk stratification for pulmonary complications across at-risk primary cancer diagnoses (AUCclinical = 0.72; AUCcomposite = 0.80, P = 0.012). Overall, this PRS approach that leverages GxT interaction effects supports late effects risk prediction among childhood cancer survivors.
Significance:
This study develops a therapy-specific polygenic risk prediction model to more precisely identify childhood cancer survivors at high risk for pulmonary complications, which could help improve risk stratification for other late effects.
Data from PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer
Authors: Hong Juyeong , Lee Ji Hoon , Zhang Zhao , Wu Yanming , Yang Mei , Liao Yiji , de la Rosa Richard , Scheirer Jessica , Pechacek Douglas , Zhang Nu , Xu Zhenming , Curiel Tyler , Tan Xi , Huang Tim H.-M. , Xu Kexin
Published: March 2023

Abstract
The immunosuppressive tumor microenvironment in some cancer types, such as luminal breast cancer, supports tumor growth and limits therapeutic efficacy. Identifying approaches to induce an immunostimulatory environment could help improve cancer treatment. Here, we demonstrate that inhibition of cancer-intrinsic EZH2 promotes antitumor immunity in estrogen receptor α–positive (ERα+) breast cancer. EZH2 is a component of the polycomb-repressive complex 2 (PRC2) complex, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). A 53-gene PRC2 activity signature was closely associated with the immune responses of ERα+ breast cancer cells. The stimulatory effects of EZH2 inhibition on immune surveillance required specific activation of type I IFN signaling. Integrative analysis of PRC2-repressed genes and genome-wide H3K27me3 landscape revealed that type I IFN ligands are epigenetically silenced by H3K27me3. Notably, the transcription factor STAT2, but not STAT1, mediated the immunostimulatory functions of type I IFN signaling. Following EZH2 inhibition, STAT2 was recruited to the promoters of IFN-stimulated genes even in the absence of the cytokines, suggesting the formation of an autocrine IFN-STAT2 axis. In patients with luminal breast cancer, high levels of EZH2 and low levels of STAT2 were associated with the worst antitumor immune responses. Collectively, this work paves the way for the development of an effective therapeutic strategy that may reverse immunosuppression in cancer.
Significance:
Inhibition of EZH2 activates a type I IFN-STAT2 signaling axis and provides a therapeutic strategy to stimulate antitumor immunity and therapy responsiveness in immunologically cold luminal breast cancer.
Data from Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer
Authors: Pirhonen Juho , Szkalisity Ábel , Hagström Jaana , Kim Yonghyo , Migh Ede , Kovács Mária , Hölttä Maarit , Peränen Johan , Seppänen Hanna , Haglund Caj , Gil Jeovanis , Rezeli Melinda , Malm Johan , Horvath Peter , Markó-Varga György , Puolakkainen Pauli , Ikonen Elina
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC. A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naïve PDAC patients (n = 14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by nonlinear label-free imaging (n = 16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.
Significance:
In clinically operable pancreatic cancer, regions distant from malignant cells already display proteomic changes related to lipid transport and metabolism that affect prognosis and may be pharmacologically targeted.
Data from Systematic Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State
Authors: Pitter Kenneth L. , Grbovic-Huezo Olivera , Joost Simon , Singhal Anupriya , Blum Melissa , Wu Katherine , Holm Matilda , Ferrena Alexander , Bhutkar Arjun , Hudson Anna , Lecomte Nicolas , de Stanchina Elisa , Chaligne Ronan , Iacobuzio-Donahue Christine A. , Pe'er Dana , Tammela Tuomas
Published: March 2023

Abstract
Intratumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including pancreatic ductal adenocarcinoma (PDAC). As PDAC portends a dire prognosis, a better understanding of the mechanisms underpinning cellular diversity in PDAC is crucial. Here, we investigated the cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics. Heterogeneity contracted significantly in two-dimensional and three-dimensional cell culture models but was restored upon orthotopic transplantation. Orthotopic transplants reproducibly acquired cell states identified in autochthonous PDAC tumors, including a basal state exhibiting coexpression and coaccessibility of epithelial and mesenchymal genes. Lineage tracing combined with single-cell transcriptomics revealed that basal cells display high plasticity in situ. This work defines the impact of cellular growth conditions on phenotypic diversity and uncovers a highly plastic cell state with the capacity to facilitate state transitions and promote intratumoral heterogeneity in PDAC.
Significance:
This work provides important insights into how different model systems of pancreatic ductal adenocarcinoma mold the phenotypic space of cancer cells, highlighting the power of in vivo models.
Data from Loss of MLL Induces Epigenetic Dysregulation of Rasgrf1 to Attenuate Kras-Driven Lung Tumorigenesis
Authors: Zhu Ling-Yu , Yuan Jun-Bo , Zhang Li , He Chun-Xiao , Lin Xiao , Xu Bin , Jin Guang-Hui
Published: March 2023

Abstract
Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations.
Significance:
Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer.
Data from Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models
Authors: Penter Livius , ten Hacken Elisa , Southard Jackson , Lareau Caleb A. , Ludwig Leif S. , Li Shuqiang , Neuberg Donna S. , Livak Kenneth J. , Wu Catherine J.
Published: March 2023

Abstract
Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models.
Significance:
mtDNA mutations can serve as natural barcodes to enable lineage tracing in murine cancer models, which can be used to provide new insights into disease biology and to identify therapeutic vulnerabilities.
Data from Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer
Authors: Riesenberg Brian P. , Hunt Elizabeth G. , Tennant Megan D. , Hurst Katie E. , Andrews Alex M. , Leddy Lee R. , Neskey David M. , Hill Elizabeth G. , Rivera Guillermo O. Rangel , Paulos Chrystal M. , Gao Peng , Thaxton Jessica E.
Published: March 2023

Abstract
Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.
Significance:
Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment.
Data from Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis
Authors: Vaishnavi Aria , Juan Joseph , Jacob Maebh , Stehn Christopher , Gardner Eric E. , Scherzer Michael T. , Schuman Sophia , Van Veen J. Edward , Murphy Brandon , Hackett Christopher S. , Dupuy Adam J. , Chmura Steven A. , van der Weyden Louise , Newberg Justin Y. , Liu Annie , Mann Karen , Rust Alistair G. , Weiss William A. , Kinsey Conan G. , Adams David J. , Grossmann Allie , Mann Michael B. , McMahon Martin
Published: March 2023

Abstract
Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty–mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/β-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non–small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression.
Significance:
Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.
Data from Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages
Authors: Alsina-Sanchis Elisenda , Mülfarth Ronja , Moll Iris , Böhn Sarah , Wiedmann Lena , Jordana-Urriza Lorea , Ziegelbauer Tara , Zimmer Eleni , Taylor Jacqueline , De Angelis Rigotti Francesca , Stögbauer Adrian , Giaimo Benedetto Daniele , Cerwenka Adelheid , Borggrefe Tilman , Fischer Andreas , Rodriguez-Vita Juan
Published: March 2023

Abstract
Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature; this was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment.
Significance:
Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.
Data from WNT5A–RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer
Authors: Kim Kee-Beom , Kim Dong-Wook , Kim Youngchul , Tang Jun , Kirk Nicole , Gan Yongyu , Kim Bongjun , Fang Bingliang , Park Jae-ll , Zheng Yi , Park Kwon-Sik
Published: March 2023

Abstract
WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models. β-Catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin–independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, whereas WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A–RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity.
Significance:
The p130–WNT5A–RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment.
Data from Aberrant L-Fucose Accumulation and Increased Core Fucosylation Are Metabolic Liabilities in Mesenchymal Glioblastoma
Authors: Pieri Valentina , Gallotti Alberto L. , Drago Denise , Cominelli Manuela , Pagano Ilaria , Conti Valentina , Valtorta Silvia , Coliva Angela , Lago Sara , Michelatti Daniela , Massimino Luca , Ungaro Federica , Perani Laura , Spinelli Antonello , Castellano Antonella , Falini Andrea , Zippo Alessio , Poliani Pietro L. , Moresco Rosa Maria , Andolfo Annapaola , Galli Rossella
Published: March 2023

Abstract
Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)–based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.

Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.
Significance:
Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.
Data from MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages
Authors: Dhanasekaran Renumathy , Hansen Aida S. , Park Jangho , Lemaitre Lea , Lai Ian , Adeniji Nia , Kuruvilla Sibu , Suresh Akanksha , Zhang Josephine , Swamy Varsha , Felsher Dean W.
Published: March 2023

Abstract
Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonresponsiveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to the recruitment of proinflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune-checkpoint responsiveness and a key driver of immune evasion through the suppression of proinflammatory macrophages. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.
Significance:
Macrophage-mediated immune evasion is a therapeutic vulnerability of MYC-driven cancers, which has implications for prioritizing MYC-driven hepatocellular carcinoma for combination immunotherapy.
Data from Pharmacological Targeting of Androgen Receptor Elicits Context-Specific Effects in Estrogen Receptor–Positive Breast Cancer
Authors: Wei Lixuan , Gao Huanyao , Yu Jia , Zhang Huan , Nguyen Thanh Thanh L. , Gu Yayun , Passow Marie R. , Carter Jodi M. , Qin Bo , Boughey Judy C. , Goetz Matthew P. , Weinshilboum Richard M. , Ingle James N. , Wang Liewei
Published: March 2023

Abstract
Androgen receptor (AR) is expressed in 80% to 90% of estrogen receptor α–positive (ER+) breast cancers. Accumulated evidence has shown that AR is a tumor suppressor and that its expression is associated with improved prognosis in ER+ breast cancer. However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In this study, we evaluated the efficacy of ENZ and RAD140 in vivo and in vitro in AR+/ER+ breast cancer models, characterizing the relationship of AR and ER levels to response to AR-targeting drugs and investigating the alterations of global gene expression and chromatin binding of AR and ERα after ENZ treatment. In the AR-low setting, ENZ directly functioned as an ERα antagonist. Cell growth inhibition by ENZ in breast cancer with low AR expression was independent of AR and instead dependent on ER. In AR-high breast cancer models, AR repressed ERα signaling and ENZ promoted ERα signaling by antagonizing AR. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist, and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio.
Significance:
The ratio of androgen receptor to estrogen receptor in breast cancer dictates the response to AR-targeted therapies, providing guidelines for developing AR-directed treatment strategies for patients with breast cancer.
Data from Depletion of Conventional Type-1 Dendritic Cells in Established Tumors Suppresses Immunotherapy Efficacy
Authors: Teijeira Alvaro , Garasa Saray , Luri-Rey Carlos , de Andrea Carlos , Gato Maria , Molina Carmen , Kaisho Tsuneyasu , Cirella Assunta , Azpilikueta Arantza , Wculek Steffanie K. , Egea Josune , Olivera Irene , Rodriguez Inmaculada , Rouzaut Ana , Verkhusha Vladislav , Valencia Karmele , Sancho David , Berraondo Pedro , Melero Ignacio
Published: March 2023

Abstract
The ability of conventional type-1 dendritic cells (cDC1) to cross-present tumor antigens to CD8+ T cells is critical for the induction of antitumor CTLs. Mice that are constitutively deficient in cDC1 cells have been reported to fail to respond to immunotherapy strategies based on checkpoint inhibitors. However, further work is needed to clarify the precise time during immunotherapy treatment that cDC1 cells are required for the beneficial effect of treatment. Here, we used a refined XCR1-DTR-Venus transgenic mouse model to acutely deplete cDC1 cells and trace their behavior using intravital microscopy. Diphtheria toxin–mediated cDC1 depletion prior to immunotherapy treatment with anti–PD-1 and/or anti-CD137 immunostimulatory mAbs completely ablated antitumor efficacy. The efficacy of adoptive T-cell therapy was also hampered by prior cDC1 depletion. After the onset of immunotherapy treatment, depletion of cDC1s only moderately reduced the therapeutic efficacy of anti–PD-1 and anti-CD137 mAbs. Intravital microscopy of liver-engrafted tumors revealed changes in the intratumoral behavior of cDC1 cells in mice receiving immunotherapy, and treatment with diphtheria toxin to deplete cDC1s impaired tumor T-cell infiltration and function. These results reveal that the functional integrity of the cDC1 compartment is required at the onset of various immunotherapies to successfully treat established tumors.
Significance:
These findings reveal the intratumoral behavior of cDC1 dendritic cells in transgenic mouse models and demonstrate that the efficacy of immunotherapy regimens is precluded by elimination of these cells.
Data from Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity
Authors: Williams Hannah L. , Dias Costa Andressa , Zhang Jinming , Raghavan Srivatsan , Winter Peter S. , Kapner Kevin S. , Ginebaugh Scott P. , Väyrynen Sara A. , Väyrynen Juha P. , Yuan Chen , Navia Andrew W. , Wang Junning , Yang Annan , Bosse Timothy L. , Kalekar Radha L. , Lowder Kristen E. , Lau Mai Chan , Elganainy Dalia , Morales-Oyarvide Vicente , Rubinson Douglas A. , Singh Harshabad , Perez Kimberly , Cleary James M. , Clancy Thomas E. , Wang Jiping , Mancias Joseph D. , Brais Lauren K. , Hill Emma R. , Kozak Margaret M. , Linehan David C. , Dunne Richard F. , Chang Daniel T. , Koong Albert C. , Hezel Aram F. , Hahn William C. , Shalek Alex K. , Aguirre Andrew J. , Nowak Jonathan A. , Wolpin Brian M.
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell–cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC.
Significance:
A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.
Supplementary Tables 4 - 5 from Imaging Features of HER2 Overexpression in Breast Cancer: A Systematic Review and Meta-analysis
Authors: Elias Sjoerd G. , Adams Arthur , Wisner Dorota J. , Esserman Laura J. , van't Veer Laura J. , Mali Willem P.Th.M. , Gilhuijs Kenneth G.A. , Hylton Nola M.
Published: March 2023

PDF file - 101KB, Supplementary Table S4 - Dynamic contrast-enhanced imaging protocols of studies reporting on magnetic resonance imaging features in relation to HER2 expression in breast cancer. Supplementary Table S5 - Diffusion-weighted imaging protocols of studies reporting on apparent diffusion coefficient in relation to HER2 expression in breast cancer.
Supplementary Results from Imaging Features of HER2 Overexpression in Breast Cancer: A Systematic Review and Meta-analysis
Authors: Elias Sjoerd G. , Adams Arthur , Wisner Dorota J. , Esserman Laura J. , van't Veer Laura J. , Mali Willem P.Th.M. , Gilhuijs Kenneth G.A. , Hylton Nola M.
Published: March 2023

PDF file - 68KB
Supplementary Table 2 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis
Authors: Curtin Karen , Lin Wei-Yu , George Rina , Katory Mark , Shorto Jennifer , Cannon-Albright Lisa A. , Smith Gillian , Bishop D. Timothy , Cox Angela , Camp Nicola J.
Published: March 2023

Supplementary Table 2 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis
Supplementary Table 1 from Can Lactase Persistence Genotype Be Used to Reassess the Relationship between Renal Cell Carcinoma and Milk Drinking? Potentials and Problems in the Application of Mendelian Randomization
Authors: Timpson Nicholas J. , Brennan Paul , Gaborieau Valérie , Moore Lee , Zaridze David , Matveev Vsevolod , Szeszenia-Dabrowska Neonilia , Lissowska Jolanta , Mates Dana , Bencko Vladimir , Foretova Lenka , Janout Vladimir , Chow Wong-Ho , Rothman Nathaniel , Boffetta Paolo , Harbord Roger M. , Davey Smith George
Published: March 2023

Supplementary Table 1 from Can Lactase Persistence Genotype Be Used to Reassess the Relationship between Renal Cell Carcinoma and Milk Drinking? Potentials and Problems in the Application of Mendelian Randomization
Related Hypothesis/Commentary from Ultraviolet Exposure and Mortality among Women in Sweden
Authors: Yang Ling , Lof Marie , Veierød Marit Bragelien , Sandin Sven , Adami Hans-Olov , Weiderpass Elisabete
Published: March 2023

Related Hypothesis/Commentary from Ultraviolet Exposure and Mortality among Women in Sweden
Supplementary Table 3 from Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma
Authors: Boyd Kevin D. , Ross Fiona M. , Chiecchio Laura , Dagrada GianPaolo , Konn Zoe J. , Tapper William J. , Walker Brian A. , Wardell Christopher P. , Gregory Walter M. , Szubert Alex J. , Davies Faith E. , Morgan Gareth J.
Published: March 2023

Supplementary Table 3 from Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma
Hypothesis/Commentary Available for This Article from What If I Don't Treat My PSA-Detected Prostate Cancer? Answers from Three Natural History Models
Authors: Gulati Roman , Wever Elisabeth M. , Tsodikov Alex , Penson David F. , Inoue Lurdes Y.T. , Katcher Jeffrey , Lee Shih-Yuan , Heijnsdijk Eveline A.M. , Draisma Gerrit , de Koning Harry J. , Etzioni Ruth
Published: March 2023

Hypothesis/Commentary Available for This Article from What If I Don't Treat My PSA-Detected Prostate Cancer? Answers from Three Natural History Models
Supplementary Table 1 from Subtype-Specific Risk of Testicular Tumors among Immigrants and Their Descendants in Sweden, 1960 to 2007
Authors: Beiki Omid , Granath Fredrik , Allebeck Peter , Akre Olof , Moradi Tahereh
Published: March 2023

Supplementary Table 1 from Subtype-Specific Risk of Testicular Tumors among Immigrants and Their Descendants in Sweden, 1960 to 2007
Supplementary Table 1 from Comparison of Two Methods for Estimating Absolute Risk of Prostate Cancer Based on Single Nucleotide Polymorphisms and Family History
Authors: Hsu Fang-Chi , Sun Jielin , Zhu Yi , Kim Seong-Tae , Jin Tao , Zhang Zheng , Wiklund Fredrik , Kader A. Karim , Zheng S. Lilly , Isaacs William , Grönberg Henrik , Xu Jianfeng
Published: March 2023

Supplementary Table 1 from Comparison of Two Methods for Estimating Absolute Risk of Prostate Cancer Based on Single Nucleotide Polymorphisms and Family History
Supplementary Appendix A from Surveillance Methods for Identifying, Characterizing, and Monitoring Tobacco Products: Potential Reduced Exposure Products as an Example
Authors: O'Connor Richard J. , Cummings K. Michael , Rees Vaughan W. , Connolly Gregory N. , Norton Kaila J. , Sweanor David , Parascandola Mark , Hatsukami Dorothy K. , Shields Peter G.
Published: March 2023

Supplementary Appendix A from Surveillance Methods for Identifying, Characterizing, and Monitoring Tobacco Products: Potential Reduced Exposure Products as an Example
Supplementary Figure 5 from Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development
Authors: Bianco-Miotto Tina , Chiam Karen , Buchanan Grant , Jindal Shalini , Day Tanya K. , Thomas Mervyn , Pickering Marie A. , O'Loughlin Melissa A. , Ryan Natalie K. , Raymond Wendy A. , Horvath Lisa G. , Kench James G. , Stricker Phillip D. , Marshall Villis R. , Sutherland Robert L. , Henshall Susan M. , Gerald William L. , Scher Howard I. , Risbridger Gail P. , Clements Judith A. , Butler Lisa M. , Tilley Wayne D. , Horsfall David J. , Ricciardelli Carmela
Published: March 2023

Supplementary Figure 5 from Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development
Supplementary Table 3 from Associations of Lifestyle Factors and Anthropometric Measures with Repeat PSA Levels During Active Surveillance/Monitoring
Authors: Burton Anya J. , Martin Richard M. , Donovan Jenny L. , Lane J. Athene , Davis Michael , Hamdy Freddie C. , Neal David E. , Tilling Kate
Published: March 2023

PDF file, 58K, Change in PSA at age 50 and Yearly increase in PSA (expressed at % difference), models based on repeat PSA measures from all men with available data.
Supplementary Table 3 from Variations in Chromosomes 9 and 6p21.3 with Risk of Non–Hodgkin Lymphoma
Authors: Wang Sophia S. , Menashe Idan , Cerhan James R. , Cozen Wendy , Severson Richard K. , Davis Scott , Hutchinson Amy , Rothman Nathaniel , Chanock Stephen J. , Bernstein Leslie , Hartge Patricia , Morton Lindsay M.
Published: March 2023

Supplementary Table 3 from Variations in Chromosomes 9 and 6p21.3 with Risk of Non–Hodgkin Lymphoma
Supplementary Table 1 from The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors
Authors: Varghese Jajini S. , Smith Paula L. , Folkerd Elizabeth , Brown Judith , Leyland Jean , Audley Tina , Warren Ruth M.L. , Dowsett Mitchell , Easton Douglas F. , Thompson Deborah J.
Published: March 2023

PDF file - 108K, Regression estimates for associations between density measures and risk factors in the SIBS cohort.
Supplementary Table 1 from Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study
Authors: Yin Jianhua , Zhang Hongwei , He Yongchao , Xie Jiaxin , Liu Shijian , Chang Wenjun , Tan Xiaojie , Gu Chunying , Lu Wei , Wang Hongyang , Bi Shengli , Cui Fuqiang , Liang Xiaofeng , Schaefer Stephan , Cao Guangwen
Published: March 2023

Supplementary Table 1 from Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study
Supplementary Figure 2 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Authors: Jemal Ahmedin , Center Melissa M. , DeSantis Carol , Ward Elizabeth M.
Published: March 2023

Supplementary Figure 2 from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Supplementary Tables 1-2 from Polymorphisms at the Microseminoprotein-β Locus Associated with Physiologic Variation in β-Microseminoprotein and Prostate-Specific Antigen Levels
Authors: Xu Xing , Valtonen-André Camilla , Sävblom Charlotta , Halldén Christer , Lilja Hans , Klein Robert J.
Published: March 2023

Supplementary Tables 1-2 from Polymorphisms at the Microseminoprotein-β Locus Associated with Physiologic Variation in β-Microseminoprotein and Prostate-Specific Antigen Levels
Supplementary Figure 1 from Generalizability and Epidemiologic Characterization of Eleven Colorectal Cancer GWAS Hits in Multiple Populations
Authors: He Jing , Wilkens Lynne R. , Stram Daniel O. , Kolonel Laurence N. , Henderson Brian E. , Wu Anna H. , Le Marchand Loic , Haiman Christopher A.
Published: March 2023

Supplementary Figure 1 from Generalizability and Epidemiologic Characterization of Eleven Colorectal Cancer GWAS Hits in Multiple Populations
Supplementary Figure Legends from Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 Are Genomic Markers for Prognosis of Advanced Nasopharyngeal Carcinoma
Authors: Sheu Jim Jinn-Chyuan , Lee Chia-Huei , Ko Jenq-Yuh , Tsao George S.W. , Wu Chung-Chun , Fang Chih-Yeu , Tsai Fuu-Jen , Hua Chun-Hung , Chen Chi-Long , Chen Jen-Yang
Published: March 2023

Supplementary Figure Legends from Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 Are Genomic Markers for Prognosis of Advanced Nasopharyngeal Carcinoma
Data from Adjuvant therapy with oncolytic adenovirus Delta-24-RGDOX after intratumoral adoptive T-cell therapy promotes antigen spread to sustain systemic antitumor immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: March 2023

Abstract
Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAAs), such as CAR T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T-cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or OVA-specific OT-I T-cells were injected into the first subcutaneous (s.c.) tumor, followed by three injections of Delta-24-RGDOX. We found TAA-targeting T-cells injected into one s.c. tumor showed tumor tropism. Delta-24-RGDOX sustained the systemic tumor regression mediated by the T-cells, leading to improved survival rate. Further analysis revealed that, in mice with disseminated B16-OVA tumors, Delta-24-RGDOX increased CD8+ leukocyte density within treated and untreated tumors. Importantly, Delta-24-RGDOX significantly reduced the immunosuppression of endogenous OVA-specific cytotoxic T lymphocytes (CTLs) while increasing that of CD8+ leukocytes and, to a lesser extent, adoptive pmel-1 T-cells. Consequently, Delta-24-RGDOX drastically increased the density of the OVA-specific CTLs in both tumors, and the combination synergistically enhanced the effect. Consistently, the splenocytes from the combination group showed a significantly stronger response against other TAAs (OVA and TRP2) than gp100, resulted in higher activity against tumor cells. Therefore, our data demonstrate that, as an adjuvant therapy followed TAA-targeting T-cells in localized treatment, Delta-24-RGDOX activates TME and promotes antigen spread, leading to efficacious systemic antitumor immunity to overcome tumor relapse.