bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Whole-Exome Sequencing Reveals Frequent Genetic Alterations in BAP1, NF2, CDKN2A, and CUL1 in Malignant Pleural Mesothelioma
Authors: Guo Guangwu , Chmielecki Juliann , Goparaju Chandra , Heguy Adriana , Dolgalev Igor , Carbone Michele , Seepo Sara , Meyerson Matthew , Pass Harvey I.
Published: March 2024

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although previous studies based on candidate gene approaches have identified important common somatic mutations in MPM, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this disease. Here, we performed whole-exome sequencing on DNA from 22 MPMs and matched blood samples, and identified 517 somatic mutations across 490 mutated genes. Integrative analysis of mutations and somatic copy-number alterations revealed frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1. Our study presents the first unbiased view of the genomic basis of MPM. Cancer Res; 75(2); 264–9. ©2014 AACR.
Data from Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis
Authors: Lin Jieru E. , Colon-Gonzalez Francheska , Blomain Erik , Kim Gilbert W. , Aing Amanda , Stoecker Brian , Rock Justin , Snook Adam E. , Zhan Tingting , Hyslop Terry M. , Tomczak Michal , Blumberg Richard S. , Waldman Scott A.
Published: March 2024

Abstract
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin–GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. Cancer Res; 76(2); 339–46. ©2016 AACR.
Data from H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis
Authors: Park Woo-Yong , Hong Beom-Jin , Lee Jungsul , Choi Chulhee , Kim Mi-Young
Published: March 2024

Abstract
Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-κB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C–C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment. Cancer Res; 76(1); 161–70. ©2016 AACR.
Data from Nucleolin Promotes Heat Shock–Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis
Authors: Morfoisse Florent , Tatin Florence , Hantelys Fransky , Adoue Aurelien , Helfer Anne-Catherine , Cassant-Sourdy Stephanie , Pujol Françoise , Gomez-Brouchet Anne , Ligat Laetitia , Lopez Frederic , Pyronnet Stephane , Courty Jose , Guillermet-Guibert Julie , Marzi Stefano , Schneider Robert J. , Prats Anne-Catherine , Garmy-Susini Barbara H.
Published: March 2024

Abstract
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5′UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394–405. ©2016 AACR.
Data from The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial–Mesenchymal Transition in Breast Cancer
Authors: Latorre Elisa , Carelli Stephana , Raimondi Ivan , D'Agostino Vito , Castiglioni Ilaria , Zucal Chiara , Moro Giacomina , Luciani Andrea , Ghilardi Giorgio , Monti Eleonora , Inga Alberto , Di Giulio Anna Maria , Gorio Alfredo , Provenzani Alessandro
Published: March 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMT in various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDA-MB-231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ER+ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes. Cancer Res; 76(9); 2626–36. ©2016 AACR.
Data from The CARMA3–Bcl10–MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor–Positive Breast Cancer
Authors: Ekambaram Prasanna , Lee Jia-Ying (Lloyd) , Hubel Nathaniel E. , Hu Dong , Yerneni Saigopalakrishna , Campbell Phil G. , Pollock Netanya , Klei Linda R. , Concel Vincent J. , Delekta Phillip C. , Chinnaiyan Arul M. , Tomlins Scott A. , Rhodes Daniel R. , Priedigkeit Nolan , Lee Adrian V. , Oesterreich Steffi , McAllister-Lucas Linda M. , Lucas Peter C.
Published: March 2024

Abstract
The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell–intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell–extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II–dependent NFκB signaling pathways to improve the treatment of this breast cancer subset.

Significance: These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. Cancer Res; 78(5); 1225–40. ©2017 AACR.
Data from Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Bachegowda Lohith , Morrone Kerry , Winski Shannon L. , Mantzaris Ioannis , Bartenstein Matthias , Ramachandra Nandini , Giricz Orsi , Sukrithan Vineeth , Nwankwo George , Shahnaz Samira , Bhagat Tushar D. , Bhattacharyya Sanchari , Assal Amer , Shastri Aditi , Gordon-Mitchell Shanisha , Pellagatti Andrea , Boultwood Jacqueline , Schinke Carolina , Yu Yiting , Guha Chandan , Rizzi James , Garrus Jennifer , Brown Suzy , Wollenberg Lance , Hogeland Grant , Wright Dale , Munson Mark , Rodriguez Mareli , Gross Stefan , Chantry David , Zou Yiyu , Platanias Leonidas C. , Burgess Laurence E. , Pradhan Kith , Steidl Ulrich , Verma Amit
Published: March 2024

Abstract
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34+ stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841–9. ©2016 AACR.
Data from Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity
Authors: Ricklefs Franz , Mineo Marco , Rooj Arun K. , Nakano Ichiro , Charest Al , Weissleder Ralph , Breakefield Xandra O. , Chiocca E. Antonio , Godlewski Jakub , Bronisz Agnieszka
Published: March 2024

Abstract
A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo. Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876–81. ©2016 AACR.
Data from Mutant p53 Promotes Epithelial Ovarian Cancer by Regulating Tumor Differentiation, Metastasis, and Responsiveness to Steroid Hormones
Authors: Ren Yi A. , Mullany Lisa K. , Liu Zhilin , Herron Alan J. , Wong Kwong-Kwok , Richards JoAnne S.
Published: March 2024

Abstract
Mutations in the tumor protein p53 (TP53) are the most frequently occurring genetic events in high-grade ovarian cancers, especially the prevalence of the Trp53R172H-mutant allele. In this study, we investigated the impact of the Trp53R172H-mutant allele on epithelial ovarian cancer (EOC) in vivo. We used the Pten/KrasG12D–mutant mouse strain that develops serous EOC with 100% penetrance to introduce the mutant Trp53R172H allele (homolog for human Trp53R172H). We demonstrate that the Trp53R172H mutation promoted EOC but had differential effects on disease features and progression depending on the presence or absence of the wild-type (WT) TP53 allele. Heterozygous WT/Trp53R172H alleles facilitated invasion into the ovarian stroma, accelerated intraperitoneal metastasis, and reduced TP53 transactivation activity but retained responsiveness to nutlin-3a, an activator of WT TP53. Moreover, high levels of estrogen receptor α in these tumors enhanced the growth of both primary and metastatic tumors in response to estradiol. Ovarian tumors homozygous for Trp53R172H mutation were undifferentiated and highly metastatic, exhibited minimal TP53 transactivation activity, and expressed genes with potential regulatory functions in EOC development. Notably, heterozygous WT/Trp53R172H mice also presented mucinous cystadenocarcinomas at 12 weeks of age, recapitulating human mucinous ovarian tumors, which also exhibit heterozygous TP53 mutations (∼50%–60%) and KRAS mutations. Therefore, we present the first mouse model of mucinous tumor formation from ovarian cells and supporting evidence that mutant TP53 is a key regulator of EOC progression, differentiation, and responsiveness to steroid hormones. Cancer Res; 76(8); 2206–18. ©2016 AACR.
Data from Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer
Authors: Herrera-Abreu Maria Teresa , Palafox Marta , Asghar Uzma , Rivas Martín A. , Cutts Rosalind J. , Garcia-Murillas Isaac , Pearson Alex , Guzman Marta , Rodriguez Olga , Grueso Judit , Bellet Meritxell , Cortés Javier , Elliott Richard , Pancholi Sunil , Lord Christopher J. , Baselga José , Dowsett Mitch , Martin Lesley-Ann , Turner Nicholas C. , Serra Violeta
Published: March 2024

Abstract
Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2–mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1–S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1–CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301–13. ©2016 AACR.
Data from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
Authors: Patel Yesha M. , Park Sunghim L. , Han Younghun , Wilkens Lynne R. , Bickeböller Heike , Rosenberger Albert , Caporaso Neil , Landi Maria Teresa , Brüske Irene , Risch Angela , Wei Yongyue , Christiani David C. , Brennan Paul , Houlston Richard , McKay James , McLaughlin John , Hung Rayjean , Murphy Sharon , Stram Daniel O. , Amos Christopher , Le Marchand Loïc
Published: March 2024

Abstract
Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3′-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10−8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768–76. ©2016 AACR.
Data from PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation
Authors: Ito Koichi , Park Sun Hee , Nayak Anupma , Byerly Jessica H. , Irie Hanna Y.
Published: March 2024

Abstract
Patients with triple-negative breast cancers (TNBC) are at high risk for recurrent or metastatic disease despite standard treatment, underscoring the need for novel therapeutic targets and strategies. Here we report that protein tyrosine kinase 6 (PTK6) is expressed in approximately 70% of TNBCs where it acts to promote survival and metastatic lung colonization. PTK6 downregulation in mesenchymal TNBC cells suppressed migration and three-dimensional culture growth, and enhanced anoikis, resistance to which is considered a prerequisite for metastasis. PTK6 downregulation restored E-cadherin levels via proteasome-dependent degradation of the E-cadherin repressor SNAIL. Beyond being functionally required in TNBC cells, kinase-active PTK6 also suppressed E-cadherin expression, promoted cell migration, and increased levels of mesenchymal markers in nontransformed MCF10A breast epithelial cells, consistent with a role in promoting an epithelial–mesenchymal transition (EMT). SNAIL downregulation and E-cadherin upregulation mediated by PTK6 inhibition induced anoikis, leading to impaired metastatic lung colonization in vivo. Finally, effects of PTK6 downregulation were phenocopied by treatment with a recently developed PTK6 kinase inhibitor, further implicating kinase activity in regulation of EMT and metastases. Our findings illustrate the clinical potential for PTK6 inhibition to improve treatment of patients with high-risk TNBC. Cancer Res; 76(15); 4406–17. ©2016 AACR.
Data from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients
Authors: Bianco Mimma , Gasparri Anna Maria , Colombo Barbara , Curnis Flavio , Girlanda Stefania , Ponzoni Maurilio , Bertilaccio Maria Teresa Sabrina , Calcinotto Arianna , Sacchi Angelina , Ferrero Elisabetta , Ferrarini Marina , Chesi Marta , Bergsagel P. Leif , Bellone Matteo , Tonon Giovanni , Ciceri Fabio , Marcatti Magda , Caligaris-Cappio Federico , Corti Angelo
Published: March 2024

Abstract
Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target. Cancer Res; 76(7); 1781–91. ©2016 AACR.
Data from Cholesterol Metabolism and Prostate Cancer Lethality
Authors: Stopsack Konrad H. , Gerke Travis A. , Sinnott Jennifer A. , Penney Kathryn L. , Tyekucheva Svitlana , Sesso Howard D. , Andersson Swen-Olof , Andrén Ove , Cerhan James R. , Giovannucci Edward L. , Mucci Lorelei A. , Rider Jennifer R.
Published: March 2024

Abstract
Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785–90. ©2016 AACR.
Data from Dietary Weight Loss and Exercise Effects on Serum Biomarkers of Angiogenesis in Overweight Postmenopausal Women: A Randomized Controlled Trial
Authors: Duggan Catherine , Tapsoba Jean de Dieu , Wang Ching-Yun , McTiernan Anne
Published: March 2024

Abstract
Obese and sedentary persons have an increased risk for cancer, but underlying mechanisms are poorly understood. Angiogenesis is common to adipose tissue formation and remodeling, and to tumor vascularization. A total of 439 overweight/obese, healthy, postmenopausal women [body mass index (BMI) > 25 kg/m2] ages 50–75 years, recruited between 2005 and 2008 were randomized to a 4-arm 12-month randomized controlled trial, comparing a caloric restriction diet arm (goal: 10% weight loss, N = 118), aerobic exercise arm (225 minutes/week of moderate-to-vigorous activity, N = 117), a combined diet + exercise arm (N = 117), or control (N = 87) on circulating levels of angiogenic biomarkers. VEGF, plasminogen activator inhibitor-1 (PAI-1), and pigment epithelium-derived factor (PEDF) were measured by immunoassay at baseline and 12 months. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity. Participants randomized to the diet + exercise arms had statistically significantly greater reductions in PAI-1 at 12 months compared with controls (−19.3% vs. +3.48%, respectively, P < 0.0001). Participants randomized to the diet and diet + exercise arms had statistically significantly greater reductions in PEDF (−9.20%, −9.90%, respectively, both P < 0.0001) and VEGF (−8.25%, P = 0.0005; −9.98%, P < 0.0001, respectively) compared with controls. There were no differences in any of the analytes in participants randomized to the exercise arm compared with controls. Increasing weight loss was statistically significantly associated with linear trends of greater reductions in PAI-1, PEDF, and VEGF. Weight loss is significantly associated with reduced circulating VEGF, PEDF, and PAI-1, and could provide incentive for reducing weight as a cancer prevention method in overweight and obese individuals. Cancer Res; 76(14); 4226–35. ©2016 AACR.
Data from Identification of MYC-Dependent Transcriptional Programs in Oncogene-Addicted Liver Tumors
Authors: Kress Theresia R. , Pellanda Paola , Pellegrinet Luca , Bianchi Valerio , Nicoli Paola , Doni Mirko , Recordati Camilla , Bianchi Salvatore , Rotta Luca , Capra Thelma , Ravà Micol , Verrecchia Alessandro , Radaelli Enrico , Littlewood Trevor D. , Evan Gerard I. , Amati Bruno
Published: March 2024

Abstract
Tumors driven by activation of the transcription factor MYC generally show oncogene addiction. However, the gene expression programs that depend upon sustained MYC activity remain unknown. In this study, we employed a mouse model of liver carcinoma driven by a reversible tet-MYC transgene, combined with chromatin immunoprecipitation and gene expression profiling to identify MYC-dependent regulatory events. As previously reported, MYC-expressing mice exhibited hepatoblastoma- and hepatocellular carcinoma–like tumors, which regressed when MYC expression was suppressed. We further show that cellular transformation, and thus initiation of liver tumorigenesis, were impaired in mice harboring a MYC mutant unable to associate with the corepressor protein MIZ1 (ZBTB17). Notably, switching off the oncogene in advanced carcinomas revealed that MYC was required for the continuous activation and repression of distinct sets of genes, constituting no more than half of all genes deregulated during tumor progression and an even smaller subset of all MYC-bound genes. Altogether, our data provide the first detailed analysis of a MYC-dependent transcriptional program in a fully developed carcinoma and offer a guide to identifying the critical effectors contributing to MYC-driven tumor maintenance. Cancer Res; 76(12); 3463–72. ©2016 AACR.
Data from Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma
Authors: Harbst Katja , Lauss Martin , Cirenajwis Helena , Isaksson Karolin , Rosengren Frida , Törngren Therese , Kvist Anders , Johansson Maria C. , Vallon-Christersson Johan , Baldetorp Bo , Borg Åke , Olsson Håkan , Ingvar Christian , Carneiro Ana , Jönsson Göran
Published: March 2024

Abstract
Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%–38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765–74. ©2016 AACR.
Data from Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients
Authors: De Monte Lucia , Wörmann Sonja , Brunetto Emanuela , Heltai Silvia , Magliacane Gilda , Reni Michele , Paganoni Anna Maria , Recalde Helios , Mondino Anna , Falconi Massimo , Aleotti Francesca , Balzano Gianpaolo , Algül Hana , Doglioni Claudio , Protti Maria Pia
Published: March 2024

Abstract
In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell–derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer. Cancer Res; 76(7); 1792–803. ©2016 AACR.
Data from Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus
Authors: Harlow Matt L. , Maloney Nichole , Roland Joseph , Guillen Navarro Maria Jose , Easton Matthew K. , Kitchen-Goosen Susan M. , Boguslawski Elissa A. , Madaj Zachary B. , Johnson Ben K. , Bowman Megan J. , D'Incalci Maurizio , Winn Mary E. , Turner Lisa , Hostetter Galen , Galmarini Carlos María , Aviles Pablo M. , Grohar Patrick J.
Published: March 2024

Abstract
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma. Cancer Res; 76(22); 6657–68. ©2016 AACR.
Data from A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies
Authors: Zhang Yongliang , Fox Jennifer T. , Park Young-Un , Elliott Gene , Rai Ganesha , Cai Mengli , Sakamuru Srilatha , Huang Ruili , Xia Menghang , Lee Kyeryoung , Jeon Min Ho , Mathew Bijoy P. , Park Hee Dong , Edelmann Winfried , Park Chan Young , Hong Sung You , Maloney David , Myung Kyungjae
Published: March 2024

Abstract
Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSα-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSα-deficient xenograft tumors and inhibits the growth of AOM-DSS–induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. Cancer Res; 76(14); 4183–91. ©2016 AACR.
Data from Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells
Authors: Wahba Amy , Rath Barbara H. , Bisht Kheem , Camphausen Kevin , Tofilon Philip J.
Published: March 2024

Abstract
Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F–cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line–specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078–87. ©2016 AACR.
Data from Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment
Authors: Ponzetta Andrea , Benigni Giorgia , Antonangeli Fabrizio , Sciumè Giuseppe , Sanseviero Emilio , Zingoni Alessandra , Ricciardi Maria Rosaria , Petrucci Maria Teresa , Santoni Angela , Bernardini Giovanni
Published: March 2024

Abstract
Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1− NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1− NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma–bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma–promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth. Cancer Res; 75(22); 4766–77. ©2015 AACR.
Data from Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer
Authors: Meder Lydia , Schuldt Philipp , Thelen Martin , Schmitt Anna , Dietlein Felix , Klein Sebastian , Borchmann Sven , Wennhold Kerstin , Vlasic Ignacija , Oberbeck Sebastian , Riedel Richard , Florin Alexandra , Golfmann Kristina , Schlößer Hans A. , Odenthal Margarete , Buettner Reinhard , Wolf Juergen , Hallek Michael , Herling Marco , von Bergwelt-Baildon Michael , Reinhardt H. Christian , Ullrich Roland T.
Published: March 2024

Abstract
Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1–targeted therapy synergistically improves treatment outcome compared with anti–PD-L1 and anti-VEGF monotherapy. Mice treated with anti–PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double-positive exhausted T-cell phenotype. This exhausted T-cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF–targeted treatment. We confirmed a similar TIM-3–positive T-cell phenotype in peripheral blood mononuclear cells of patients with SCLC with adaptive resistance to anti–PD-1 treatment. Mechanistically, we show that VEGFA enhances coexpression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in patients with SCLC during anti–PD-1-targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti–PD-L1 therapies can be an effective treatment strategy in patients with SCLC.

Significance: Combining VEGF and PD-L1 blockade could be of therapeutic benefit to patients with small cell lung cancer. Cancer Res; 78(15); 4270–81. ©2018 AACR.
Data from TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis
Authors: Principe Daniel R. , DeCant Brian , Mascariñas Emman , Wayne Elizabeth A. , Diaz Andrew M. , Akagi Naomi , Hwang Rosa , Pasche Boris , Dawson David W. , Fang Deyu , Bentrem David J. , Munshi Hidayatullah G. , Jung Barbara , Grippo Paul J.
Published: March 2024

Abstract
In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8+ T cells led to enhanced infiltration and granzyme B–mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525–39. ©2016 AACR.
Data from Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth
Authors: Gross-Cohen Miriam , Feld Sari , Doweck Ilana , Neufeld Gera , Hasson Peleg , Arvatz Gil , Barash Uri , Naroditsky Inna , Ilan Neta , Vlodavsky Israel
Published: March 2024

Abstract
The endoglycosidase heparanase specifically cleaves the heparan sulfate (HS) side chains on proteoglycans, an activity that has been implicated strongly in tumor metastasis and angiogenesis. Heparanase-2 (Hpa2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. In head and neck cancer patients, Hpa2 expression was markedly elevated, correlating with prolonged time to disease recurrence and inversely correlating with tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions as a tumor suppressor. The molecular mechanism associated with favorable prognosis following Hpa2 induction is unclear. Here we provide evidence that Hpa2 overexpression in head and neck cancer cells markedly reduces tumor growth. Restrained tumor growth was associated with a prominent decrease in tumor vascularity (blood and lymph vessels), likely due to reduced Id1 expression, a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation. We also noted that tumors produced by Hpa2-overexpressing cells are abundantly decorated with stromal cells and collagen deposition, correlating with a marked increase in lysyl oxidase expression. Notably, heparanase enzymatic activity was unimpaired in cells overexpressing Hpa2, suggesting that reduced tumor growth is not caused by heparanase regulation. Moreover, growth of tumor xenografts by Hpa2-overexpressing cells was unaffected by administration of a mAb that targets the heparin-binding domain of Hpa2, implying that Hpa2 function does not rely on heparanase or heparan sulfate. Cancer Res; 76(9); 2791–801. ©2016 AACR.