bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Hypothermia Effectively Treats Tumors with Temperature-Sensitive p53 Mutations
Authors: Lu Junhao , Chen Lihong , Song Zheng , Das Mousumi , Chen Jiandong
Published: March 2023

Abstract
The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 mutations are located in the DNA-binding domain, causing local disruption of DNA-binding surface or global misfolding. Rescuing the structural defect of mutant p53 is an attractive therapeutic strategy, but its potential remains unproven due to a lack of drugs capable of efficiently rescuing misfolded p53. Although mutant p53 in tumors is inactive at 37°C, approximately 15% are temperature sensitive (ts) and regain DNA-binding activity at 32°C to 34°C (ts mutants). This temperature is achievable using a therapeutic hypothermia procedure established for resuscitated cardiac arrest patients. To test whether hypothermia can be used to target tumors with ts p53 mutations, the core temperature of tumor-bearing mice was lowered to 32°C using the adenosine A1 receptor agonist N6-cyclohexyladenoxine that suppresses brain-regulated thermogenesis. Hypothermia treatment (32 hours at 32°C × 5 cycles) activated endogenous ts mutant p53 in xenograft tumors and inhibited tumor growth in a p53-dependent fashion. Tumor regression and durable remission in a ts p53 lymphoma model was achieved by combining hypothermia with chemotherapy. The results raise the possibility of treating tumors expressing ts p53 mutations with hypothermia.
Significance:
Pharmacologic inhibition of brain-regulated thermogenesis and induction of 32°C whole-body hypothermia specifically targets tumors with temperature-sensitive p53 mutations, rescuing p53 transcriptional activity and inducing tumor regression.

See related commentary by Hu and Feng, p. 3762
Data from Sleeping Beauty Transposon Mutagenesis Identifies Genes Driving the Initiation and Metastasis of Uterine Leiomyosarcoma
Authors: Kodama Michiko , Shimura Hiroko , Tien Jean C. , Newberg Justin Y. , Kodama Takahiro , Wei Zhubo , Rangel Roberto , Yoshihara Kosuke , Kuruma Airi , Nakae Aya , Hashimoto Kae , Sawada Kenjiro , Kimura Tadashi , Jenkins Nancy A. , Copeland Neal G.
Published: March 2023

Abstract
Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium–specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy.
Significance:
An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets.
Data from Locus-Specific Characterization of Human Endogenous Retrovirus Expression in Prostate, Breast, and Colon Cancers
Authors: Steiner Margaret C. , Marston Jez L. , Iñiguez Luis P. , Bendall Matthew L. , Chiappinelli Katherine B. , Nixon Douglas F. , Crandall Keith A.
Published: March 2023

Abstract
Human endogenous retroviruses (HERV) have been implicated in a variety of diseases including cancers. Recent research implicates HERVs in epigenetic gene regulation. Here we utilize a recently developed bioinformatics tool for identifying HERV expression at the locus-specific level to identify differential expression of HERVs in matched tumor-normal RNA-sequencing (RNA-seq) data from The Cancer Genome Atlas. Data from 52 prostate cancer, 111 breast cancer, and 24 colon cancer cases were analyzed. Locus-specific analysis identified active HERV elements and differentially expressed HERVs in prostate cancer, breast cancer, and colon cancer. In addition, differentially expressed host genes were identified across prostate, breast, and colon cancer datasets, respectively, including several involved in demethylation and antiviral response pathways, supporting previous findings regarding the pathogenic mechanisms of HERVs. A majority of differentially expressed HERVs intersected protein coding genes or lncRNAs in each dataset, and a subset of differentially expressed HERVs intersected differentially expressed genes in prostate, breast, and colon cancers, providing evidence towards regulatory function. Finally, patterns in HERV expression were identified in multiple cancer types, with 155 HERVs differentially expressed in all three cancer types. This analysis extends previous results identifying HERV transcription in cancer RNA-seq datasets to a locus-specific level, and in doing so provides a foundation for future studies investigating the functional role of HERV in cancers and identifies a number of novel targets for cancer biomarkers and immunotherapy.
Significance:
Expressed human endogenous retroviruses are mapped at locus-specific resolution and linked to specific pathways to identify potential biomarkers and therapeutic targets in prostate, breast, and colon cancers.
Data from A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
Authors: Emami Nima C. , Cavazos Taylor B. , Rashkin Sara R. , Cario Clinton L. , Graff Rebecca E. , Tai Caroline G. , Mefford Joel A. , Kachuri Linda , Wan Eunice , Wong Simon , Aaronson David , Presti Joseph , Habel Laurel A. , Shan Jun , Ranatunga Dilrini K. , Chao Chun R. , Ghai Nirupa R. , Jorgenson Eric , Sakoda Lori C. , Kvale Mark N. , Kwok Pui-Yan , Schaefer Catherine , Risch Neil , Hoffmann Thomas J. , Van Den Eeden Stephen K. , Witte John S.
Published: March 2023

Abstract
To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits.
Significance:
This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.

See related commentary by Lachance, p. 1637
Data from Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD
Authors: Tu Hsin-Fang , Ko Chun-Jung , Lee Ching-Tai , Lee Cheng-Fan , Lan Shao-Wei , Lin Hsin-Hsien , Lin Hsin-Ying , Ku Chia-Chi , Lee Der-Yen , Chen I-Chun , Chuang Ya-Hui , Del Caño-Ochoa Francisco , Ramón-Maiques Santiago , Ho Chao-Chi , Lee Ming-Shyue , Chang Geen-Dong
Published: March 2023

Abstract
Current clinical trials of combined EGFR-tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8+ T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8+ T lymphocyte proliferation, and we identify CAD, a key enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)–bearing mice. Early afatinib treatment inhibited CD8+ T lymphocyte proliferation in patients with non–small cell lung cancer, but their proliferation unexpectedly rebounded following long-term treatment. This suggests a transient immunomodulatory effect of afatinib on CD8+ T lymphocytes. Sequential treatment of afatinib with anti-PD1 immunotherapy substantially enhanced therapeutic efficacy in MC38 and LLC-bearing mice, while simultaneous combination therapy showed only marginal improvement over each single treatment. These results suggest that afatinib can suppress CD8+ T lymphocyte proliferation by targeting CAD, proposing a timing window for combined therapy that may prevent the dampening of ICB efficacy by EGFR-TKIs.
Significance:
This study elucidates a mechanism of afatinib-mediated immunosuppression and provides new insights into treatment timing for combined targeted therapy and immunotherapy.
Data from High-Density, Targeted Monitoring of Tyrosine Phosphorylation Reveals Activated Signaling Networks in Human Tumors
Authors: Stopfer Lauren E. , Flower Cameron T. , Gajadhar Aaron S. , Patel Bhavin , Gallien Sebastien , Lopez-Ferrer Daniel , White Forest M.
Published: March 2023

Abstract
Tyrosine phosphorylation (pTyr) plays a pivotal role in signal transduction and is commonly dysregulated in cancer. As a result, profiling tumor pTyr levels may reveal therapeutic insights critical to combating disease. Existing discovery and targeted mass spectrometry–based methods used to monitor pTyr networks involve a tradeoff between broad coverage of the pTyr network, reproducibility in target identification across analyses, and accurate quantification. To address these limitations, we developed a targeted approach, termed “SureQuant pTyr,” coupling low input pTyr enrichment with a panel of isotopically labeled internal standard peptides to guide data acquisition of low-abundance tyrosine phosphopeptides. SureQuant pTyr allowed for reliable quantification of several hundred commonly dysregulated pTyr targets with high quantitative accuracy, improving the robustness and usability of targeted mass spectrometry assays. We established the clinical applicability of SureQuant pTyr by profiling pTyr signaling levels in human colorectal tumors using minimal sample input, characterizing patient-specific oncogenic-driving mechanisms. While in some cases pTyr profiles aligned with previously reported proteomic, genomic, and transcriptomic molecular characterizations, we highlighted instances of new insights gained using pTyr characterization and emphasized the complementary nature of pTyr measurements with traditional biomarkers for improving patient stratification and identifying therapeutic targets. The turn-key nature of this approach opens the door to rapid and reproducible pTyr profiling in research and clinical settings alike and enables pTyr-based measurements for applications in precision medicine.
Significance:
SureQuant pTyr is a mass spectrometry–based targeted method that enables sensitive and selective targeted quantitation of several hundred low-abundance tyrosine phosphorylated peptides commonly dysregulated in cancer, including oncogenic signaling networks.
Data from Multiparametric Photoacoustic Analysis of Human Thyroid Cancers In Vivo
Authors: Kim Jeesu , Park Byullee , Ha Jeonghoon , Steinberg Idan , Hooper Sarah M. , Jeong Chaiho , Park Eun-Yeong , Choi Wonseok , Liang Tie , Bae Ja Seong , Managuli Ravi , Kim Yongmin , Gambhir Sanjiv S. , Lim Dong-Jun , Kim Chulhong
Published: March 2023

Abstract
Thyroid cancer is one of the most common cancers, with a global increase in incidence rate for both genders. Ultrasound-guided fine-needle aspiration is the current gold standard to diagnose thyroid cancers, but the results are inaccurate, leading to repeated biopsies and unnecessary surgeries. To reduce the number of unnecessary biopsies, we explored the use of multiparametric photoacoustic (PA) analysis in combination with the American Thyroid Association (ATA) Guideline (ATAP). In this study, we performed in vivo multispectral PA imaging on thyroid nodules from 52 patients, comprising 23 papillary thyroid cancer (PTC) and 29 benign cases. From the multispectral PA data, we calculated hemoglobin oxygen saturation level in the nodule area, then classified the PTC and benign nodules with multiparametric analysis. Statistical analyses showed that this multiparametric analysis of multispectral PA responses could classify PTC nodules. Combining the photoacoustically indicated probability of PTC and the ATAP led to a new scoring method that achieved a sensitivity of 83% and a specificity of 93%. This study is the first multiparametric analysis of multispectral PA data of thyroid nodules with statistical significance. As a proof of concept, the results show that the proposed new ATAP scoring can help physicians examine thyroid nodules for fine-needle aspiration biopsy, thus reducing unnecessary biopsies.
Significance:
This report highlights a novel photoacoustic scoring method for risk stratification of thyroid nodules, where malignancy of the nodules can be diagnosed with 83% sensitivity and 93% specificity.
Data from Hedgehog Signaling Regulates Metabolism and Polarization of Mammary Tumor-Associated Macrophages
Authors: Hinshaw Dominique C. , Hanna Ann , Lama-Sherpa Tshering , Metge Brandon , Kammerud Sarah C. , Benavides Gloria A. , Kumar Atul , Alsheikh Heba Allah , Mota Mateus , Chen Dongquan , Ballinger Scott W. , Rathmell Jeffrey C. , Ponnazhagan Selvarangan , Darley-Usmar Victor , Samant Rajeev S. , Shevde Lalita A.
Published: March 2023

Abstract
Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacologic Hh inhibitor vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune-suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited.
Significance:
These findings illustrate that Hh activity regulates a metabolic and bioenergetic regulatory program in tumor-associated macrophages that promotes their immune-suppressive polarization.
Data from Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model
Authors: Hung Rayjean J. , Warkentin Matthew T. , Brhane Yonathan , Chatterjee Nilanjan , Christiani David C. , Landi Maria Teresa , Caporaso Neil E. , Liu Geoffrey , Johansson Mattias , Albanes Demetrius , Marchand Loic Le , Tardon Adonina , Rennert Gad , Bojesen Stig E. , Chen Chu , Field John K. , Kiemeney Lambertus A. , Lazarus Philip , Zienolddiny Shanbeth , Lam Stephen , Andrew Angeline S. , Arnold Susanne M. , Aldrich Melinda C. , Bickeböller Heike , Risch Angela , Schabath Matthew B. , McKay James D. , Brennan Paul , Amos Christopher I.
Published: March 2023

Abstract
Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data (N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92–3.00; P = 1.80 × 10−14] in the validation set (Ptrend = 5.26 × 10−20). The OR per SD of PRS increase was 1.26 (95% CI = 1.20–1.32; P = 9.69 × 10−23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy.
Significance:
Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
Data from A MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma
Authors: Tartey Sarang , Neale Geoffrey , Vogel Peter , Malireddi R.K. Subbarao , Kanneganti Thirumala-Devi
Published: March 2023

Abstract
Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are generally associated with tumor-promoting immunosuppressive functions in solid tumors. Here, we examined the transcriptional landscape of adaptor molecules downstream of Toll-like receptors in human cancers and found that higher expression of MYD88 correlated with tumor progression. In murine melanoma, MyD88, but not Trif, was essential for tumor progression, angiogenesis, and maintaining the immunosuppressive phenotype of TAMs. In addition, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/IL1 receptor (IL1R) axis regulated programmed cell death (PD)-1 expression on TAMs by promoting recruitment of NF-κBp65 to the Pdcd1 promoter. Furthermore, a combinatorial immunotherapy approach combining the MyD88 inhibitor with anti–PD-1 blockade elicited strong antitumor effects. Thus, the MyD88/IL1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression.
Significance:
These findings indicate that MyD88 regulates TAM-immunosuppressive activity, suggesting that macrophage-mediated immunotherapy combining MYD88 inhibitors with PD-1 blockade could result in better treatment outcomes in a wide variety of cancers.
Data from Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity
Authors: Seclì Laura , Avalle Lidia , Poggio Pietro , Fragale Giuseppe , Cannata Cristiana , Conti Laura , Iannucci Andrea , Carrà Giovanna , Rubinetto Cristina , Miniscalco Barbara , Hirsch Emilio , Poli Valeria , Morotti Alessandro , De Andrea Marco , Turco Emilia , Cavallo Federica , Fusella Federica , Brancaccio Mara
Published: March 2023

Abstract
HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a mAb targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8+ T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, these data define Morgana as a new player in the HSP90 extracellular interactome and suggest that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress antitumor immunity.
Significance:
This work suggests the potential therapeutic value of targeting the extracellular HSP90 co-chaperone Morgana to inhibit metastasis formation and enhance the CD8+ T-cell–mediated antitumor immune response.
Data from RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer
Authors: Arnold Frank , Gout Johann , Wiese Heike , Weissinger Stephanie E. , Roger Elodie , Perkhofer Lukas , Walter Karolin , Scheible Jeanette , Prelli Bozzo Caterina , Lechel André , Ettrich Thomas J. , Azoitei Ninel , Hao Li , Fürstberger Axel , Kaminska Ewa K. , Sparrer Konstantin M.J. , Rasche Volker , Wiese Sebastian , Kestler Hans A. , Möller Peter , Seufferlein Thomas , Frappart Pierre-Olivier , Kleger Alexander
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G2 cell cycle arrest, disruption of Golgi–endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach.
Significance:
These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.
Data from Diet Alters Entero-Mammary Signaling to Regulate the Breast Microbiome and Tumorigenesis
Authors: Soto-Pantoja David R. , Gaber Mohamed , Arnone Alana A. , Bronson Steven M. , Cruz-Diaz Nildris , Wilson Adam S. , Clear Kenysha Y.J. , Ramirez Manuel U. , Kucera Gregory L. , Levine Edward A. , Lelièvre Sophie A. , Chaboub Lesley , Chiba Akiko , Yadav Hariom , Vidi Pierre-Alexandre , Cook Katherine L.
Published: March 2023

Abstract
Obesity and poor diet often go hand-in-hand, altering metabolic signaling and thereby impacting breast cancer risk and outcomes. We have recently demonstrated that dietary patterns modulate mammary microbiota populations. An important and largely open question is whether the microbiome of the gut and mammary gland mediates the dietary effects on breast cancer. To address this, we performed fecal transplants between mice on control or high-fat diets (HFD) and recorded mammary tumor outcomes in a chemical carcinogenesis model. HFD induced protumorigenic effects, which could be mimicked in animals fed a control diet by transplanting HFD-derived microbiota. Fecal transplants altered both the gut and mammary tumor microbiota populations, suggesting a link between the gut and breast microbiomes. HFD increased serum levels of bacterial lipopolysaccharide (LPS), and control diet–derived fecal transplant reduced LPS bioavailability in HFD-fed animals. In vitro models of the normal breast epithelium showed that LPS disrupts tight junctions (TJ) and compromises epithelial permeability. In mice, HFD or fecal transplant from animals on HFD reduced expression of TJ-associated genes in the gut and mammary gland. Furthermore, infecting breast cancer cells with an HFD-derived microbiome increased proliferation, implicating tumor-associated bacteria in cancer signaling. In a double-blind placebo-controlled clinical trial of patients with breast cancer administered fish oil supplements before primary tumor resection, dietary intervention modulated the microbiota in tumors and normal breast tissue. This study demonstrates a link between the gut and breast that mediates the effect of diet on cancer.
Significance:
This study demonstrates that diet shifts the microbiome in the gut and the breast tumor microenvironment to affect tumorigenesis, and oral dietary interventions can modulate the tumor microbiota in patients with breast cancer.
Data from Premalignant Oligodendrocyte Precursor Cells Stall in a Heterogeneous State of Replication Stress Prior to Gliomagenesis
Authors: Sutcliffe Matthew D. , Galvao Rui P. , Wang Lixin , Kim Jungeun , Rosenfeld Lauren K. , Singh Shambhavi , Zong Hui , Janes Kevin A.
Published: March 2023

Abstract
Cancer evolves from premalignant clones that adopt unusual cell states to achieve transformation. We previously pinpointed the oligodendrocyte precursor cell (OPC) as a cell of origin for glioma, but the early changes of mutant OPCs during premalignancy remained unknown. Using mice engineered for inducible Nf1-Trp53 loss in OPCs, we acutely isolated labeled mutant OPCs by laser-capture microdissection, determined global gene-expression changes by bulk RNA sequencing, and compared with cell-state fluctuations at the single-cell level by stochastic profiling, which uses RNA-sequencing measurements from random pools of 10 mutant cells. At 12 days after Nf1-Trp53 deletion, bulk differences were mostly limited to mitotic hallmarks and genes for ribosome biosynthesis, and stochastic profiling revealed a spectrum of stem-progenitor (Axl, Aldh1a1), proneural, and mesenchymal states as potential starting points for gliomagenesis. At 90 days, bulk sequencing detected few differentially expressed transcripts, whereas stochastic profiling revealed cell states for neurons and mural cells that do not give rise to glial tumors, suggesting cellular dead-ends for gliomagenesis. Importantly, mutant OPCs that strongly expressed key effectors of nonsense-mediated decay (Upf3b) and homology-dependent DNA repair (Rad51c, Slx1b, Ercc4) were identified along with DNA-damage markers, suggesting transcription-associated replication stress. Analysis of 10-cell transcriptomes at 90 days identified a locus of elevated gene expression containing an additional repair endonuclease (Mus81) and Rin1, a Ras-Raf antagonist and possible counterbalance to Nf1 loss, which was microdeleted or downregulated in gliomas at 150 days. These hidden cell-state variations uncover replication stress as a potential bottleneck that must be resolved for glioma initiation.
Significance:
Profiling premalignant cell states in a mouse model of glioma uncovers regulatory heterogeneity in glioma cells-of-origin and defines a state of replication stress that precedes tumor initiation.

See related articles by Singh and colleagues, p. 1840 and Schaff and colleagues, p. 1853
Data from Endothelial Reprogramming Stimulated by Oncostatin M Promotes Inflammation and Tumorigenesis in VHL-Deficient Kidney Tissue
Authors: Nguyen-Tran Hieu-Huy , Nguyen Thi-Ngoc , Chen Chen-Yun , Hsu Tien
Published: March 2023

Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor-α (HIFα), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (EC), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL-deficient renal tubule cells and the ECs, and the activated ECs in turn induced macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL-deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression.
Significance:
A novel mechanism of cross-talk between ECs and VHL-deficient kidney tubules that stimulates inflammation and tumorigenesis is discovered, suggesting OSM could be a potential target for ccRCC intervention.
Data from Targeting the HuR Oncogenic Role with a New Class of Cytoplasmic Dimerization Inhibitors
Authors: Filippova Natalia , Yang Xiuhua , Ananthan Subramaniam , Calano Jennifer , Pathak Vibha , Bratton Larry , Vekariya Rakesh H. , Zhang Sixue , Ofori Edward , Hayward Emily N. , Namkoong David , Crossman David K. , Crowley Michael R. , King Peter H. , Mobley James , Nabors Louis B.
Published: March 2023

Abstract
The development of novel therapeutics that exploit alterations in the activation state of key cellular signaling pathways due to mutations in upstream regulators has generated the field of personalized medicine. These first-generation efforts have focused on actionable mutations identified by deep sequencing of large numbers of tumor samples. We propose that a second-generation opportunity exists by exploiting key downstream “nodes of control” that contribute to oncogenesis and are inappropriately activated due to loss of upstream regulation and microenvironmental influences. The RNA-binding protein HuR represents such a node. Because HuR functionality in cancer cells is dependent on HuR dimerization and its nuclear/cytoplasmic shuttling, we developed a new class of molecules targeting HuR protein dimerization. A structure–activity relationship algorithm enabled development of inhibitors of HuR multimer formation that were soluble, had micromolar activity, and penetrated the blood–brain barrier. These inhibitors were evaluated for activity validation and specificity in a robust cell-based assay of HuR dimerization. SRI-42127, a molecule that met these criteria, inhibited HuR multimer formation across primary patient-derived glioblastoma xenolines (PDGx), leading to arrest of proliferation, induction of apoptosis, and inhibition of colony formation. SRI-42127 had favorable attributes with central nervous system penetration and inhibited tumor growth in mouse models. RNA and protein analysis of SRI-42127–treated PDGx xenolines across glioblastoma molecular subtypes confirmed attenuation of targets upregulated by HuR. These results highlight how focusing on key attributes of HuR that contribute to cancer progression, namely cytoplasmic localization and multimerization, has led to the development of a novel, highly effective inhibitor.
Significance:
These findings utilize a cell-based mechanism of action assay with a structure–activity relationship compound development pathway to discover inhibitors that target HuR dimerization, a mechanism required for cancer promotion.
Data from α1-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages
Authors: Matsusaka Kotaro , Fujiwara Yukio , Pan Cheng , Esumi Shigeyuki , Saito Yoichi , Bi Jing , Nakamura Yuka , Mukunoki Ayumi , Takeo Toru , Nakagata Naomi , Yoshii Daiki , Fukuda Ryo , Nagasaki Taisei , Tanaka Ryusei , Komori Hisakazu , Maeda Hitoshi , Watanabe Hiroshi , Tamada Koji , Komohara Yoshihiro , Maruyama Toru
Published: March 2023

Abstract
Blood levels of acute-phase protein α1-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell–derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte–derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy.
Significance:
AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.
Data from Light at Night and Risk of Pancreatic Cancer in the NIH-AARP Diet and Health Study
Authors: Xiao Qian , Jones Rena R. , James Peter , Stolzenberg-Solomon Rachael Z.
Published: March 2023

Abstract
Circadian disruption may play a role in carcinogenesis. Recent research suggests that light at night (LAN), a circadian disruptor, may be a risk factor for cancer. Moreover, LAN has been linked to obesity and diabetes, two risk factors for pancreatic ductal adenocarcinoma (PDAC). Here we examine the relationship between LAN and PDAC in an epidemiologic study of 464,371 participants from the NIH-AARP Diet and Health Study. LAN was estimated from satellite imagery at baseline (1996), and incident primary PDAC cases were ascertained from state cancer registries. Cox proportional hazards models were used to estimate HRs and two-sided 95% confidence intervals (CI) for the association between quintiles of LAN and PDAC in the overall population stratified by sex. Over up to 16.2 years of follow-up, a total of 2,502 incident PDAC were identified in the cohort. Higher estimated LAN exposure was associated with an elevated PDAC risk. Compared with those living in areas in the lowest LAN quintile, those in areas in the highest quintile had a 27% increase PDAC risk [HR (95% CI), 1.24 (1.03–1.49)], with similar risk for men [1.21 (0.96–1.53)] and women [1.28 (0.94–1.75)]. In addition, stronger associations were observed in normal and overweight groups compared with the obese group (Pinteraction = 0.03). Our results support the hypothesis that LAN and circadian disruption may be risk factors for PDAC.
Significance:
Our study suggests that higher LAN is a risk factor for pancreatic cancer, contributing to the growing literature that demonstrates the potentially adverse health effects of light pollution.
Data from NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis
Authors: Zhao Zhenjun , Gad Helge , Benitez-Buelga Carlos , Sanjiv Kumar , Xiangwei Hua , Kang He , Feng Mingxuan , Zhao Zhicong , Berglund Ulrika Warpman , Xia Qiang , Helleday Thomas
Published: March 2023

Abstract
Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC.
Significance:
This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.
Data from Gut Microbiota–Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling
Authors: Matsushita Makoto , Fujita Kazutoshi , Hayashi Takuji , Kayama Hisako , Motooka Daisuke , Hase Hiroaki , Jingushi Kentaro , Yamamichi Gaku , Yumiba Satoru , Tomiyama Eisuke , Koh Yoko , Hayashi Yujiro , Nakano Kosuke , Wang Cong , Ishizuya Yu , Kato Taigo , Hatano Koji , Kawashima Atsunari , Ujike Takeshi , Uemura Motohide , Imamura Ryoichi , Rodriguez Pena Maria D.C. , Gordetsky Jennifer B. , Netto George J. , Tsujikawa Kazutake , Nakamura Shota , Takeda Kiyoshi , Nonomura Norio
Published: March 2023

Abstract
Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota–mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer–bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment.
Significance:
These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.
Data from In Vivo Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification
Authors: Xie Jinghang , Rice Meghan A. , Chen Zixin , Cheng Yunfeng , Hsu En-Chi , Chen Min , Song Guosheng , Cui Liyang , Zhou Kaixiang , Castillo Jessa B. , Zhang Chiyuan A. , Shen Bin , Chin Frederick T. , Kunder Christian A. , Brooks James D. , Stoyanova Tanya , Rao Jianghong
Published: March 2023

Abstract
Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical for improving treatment decisions and patient survival. In this study, we analyzed radical prostatectomy specimens from 422 patients with localized disease to define the expression pattern of methionine aminopeptidase II (MetAP2), a cytosolic metalloprotease that has been identified as a druggable target in cancer. MetAP2 was highly expressed in 54% of low-grade and 59% of high-grade cancers. Elevated levels of MetAP2 at diagnosis were associated with shorter time to recurrence. Controlled self-assembly of a synthetic small molecule enabled design of the first MetAP2-activated PET imaging tracer for monitoring MetAP2 activity in vivo. The nanoparticles assembled upon MetAP2 activation were imaged in single prostate cancer cells with post-click fluorescence labeling. The fluorine-18–labeled tracers successfully differentiated MetAP2 activity in both MetAP2-knockdown and inhibitor-treated human prostate cancer xenografts by micro-PET/CT scanning. This highly sensitive imaging technology may provide a new tool for noninvasive early-risk stratification of prostate cancer and monitoring the therapeutic effect of MetAP2 inhibitors as anticancer drugs.
Significance:
This study defines MetAP2 as an early-risk stratifier for molecular imaging of aggressive prostate cancer and describes a MetAP2-activated self-assembly small-molecule PET tracer for imaging MetAP2 activity in vivo.
Data from GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy
Authors: Ancey Pierre-Benoit , Contat Caroline , Boivin Gael , Sabatino Silvia , Pascual Justine , Zangger Nadine , Perentes Jean Yannis , Peters Solange , Abel E. Dale , Kirsch David G. , Rathmell Jeffrey C. , Vozenin Marie-Catherine , Meylan Etienne
Published: March 2023

Abstract
Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils.
Significance:
Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells.
Data from Epigenetic Alterations and Mechanisms That Drive Resistance to Targeted Cancer Therapies
Authors: Wajapeyee Narendra , Gupta Romi
Published: March 2023

Abstract
Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some patients with cancer experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell nonautonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.