bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Information from Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death
Authors: Cottone Lucia , Cribbs Adam P. , Khandelwal Garima , Wells Graham , Ligammari Lorena , Philpott Martin , Tumber Anthony , Lombard Patrick , Hookway Edward S. , Szommer Tamas , Johansson Catrine , Brennan Paul E. , Pillay Nischalan , Jenner Richard G. , Oppermann Udo , Flanagan Adrienne M.
Published: April 2023

Supplementary Information
Supplementary Figure S2 from E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer
Authors: López-Menéndez Celia , Vázquez-Naharro Alberto , Santos Vanesa , Dubus Pierre , Santamaría Patricia G. , Martínez-Ramírez Ángel , Portillo Francisco , Moreno-Bueno Gema , Faraldo Marisa M. , Cano Amparo
Published: April 2023

Figure S2 and legend
Supplementary Figure S1 from E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer
Authors: López-Menéndez Celia , Vázquez-Naharro Alberto , Santos Vanesa , Dubus Pierre , Santamaría Patricia G. , Martínez-Ramírez Ángel , Portillo Francisco , Moreno-Bueno Gema , Faraldo Marisa M. , Cano Amparo
Published: April 2023

Figure S1 and legend
Supplementary Data from Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity
Authors: Xu Feifei , Wang Zining , Zhang Hongxia , Chen Jiemin , Wang Xiaojuan , Cui Lei , Xie Chunyuan , Li Mengyun , Wang Fang , Zhou Penghui , Liu Jinyun , Huang Peng , Xia Xiaodong , Xia Xiaojun
Published: April 2023

Supplementary Data
Supplemental Tables 1-7 from 14-3-3σ Functions as an Intestinal Tumor Suppressor
Authors: Winter Markus , Rokavec Matjaž , Hermeking Heiko
Published: April 2023

Supplemental Tables 1-7
Data from RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2
Authors: Wang Hongyan , Liu Kaihua , Geng Miao , Gao Peng , Wu Xiaoyuan , Hai Yan , Li Yangxia , Li Yulong , Luo Lin , Hayes John D. , Wang Xiu Jun , Tang Xiuwen
Published: April 2023

Abstract
The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRα) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRα increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRα decreased ARE-driven gene expression. Biochemical investigations showed that RXRα interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRα bound to ARE sequences in the promoters of NRF2-regulated genes. RXRα loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRα and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non–small cell lung cancer cells where NRF2 levels are elevated, RXRα expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRα diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10); 3097–108. ©2013 AACR.
Data from CDK1 Regulates Mediator of DNA Damage Checkpoint 1 during Mitotic DNA Damage
Authors: Yu Bing , Dalton W. Brian , Yang Vincent W.
Published: April 2023

Abstract
Cells engage sophisticated programs of DNA damage response (DDR) and repair to guard against genetic mutations. Although there is significant knowledge concerning DDR in interphase cells, much less is known about these processes in mitosis. Direct interaction between MDC1, a master DDR organizer, and a marker of DNA damage, histone γH2AX, is required to trigger robust repair. Here we show that the DNA damage-induced interaction between MDC1 and γH2AX is attenuated in mitosis. Furthermore, inhibition in the activity of the core mitotic regulator CDK1, either by pharmacologic inhibition or siRNA attenuation, enhances MDC1–γH2AX colocalization in mitosis. Our findings offer key new insights into how DDR is controlled during mitosis. Cancer Res; 72(21); 5448–53. ©2012 AACR.
Data from Interactions of Abiraterone, Eplerenone, and Prednisolone with Wild-type and Mutant Androgen Receptor: A Rationale for Increasing Abiraterone Exposure or Combining with MDV3100
Authors: Richards Juliet , Lim Ai Chiin , Hay Colin W. , Taylor Angela E. , Wingate Anna , Nowakowska Karolina , Pezaro Carmel , Carreira Suzanne , Goodall Jane , Arlt Wiebke , McEwan Iain J. , de Bono Johann S. , Attard Gerhardt
Published: April 2023

Abstract
Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an antiandrogen. Abiraterone, a rationally designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires coadministration with glucocorticoids to curtail side effects. Here, we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess, can also bind to and activate signaling through wild-type or mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. In fact, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide, or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism. Cancer Res; 72(9); 2176–82. ©2012 AACR.
Data from Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer
Authors: Hartikainen Jaana M. , Tengström Maria , Kosma Veli-Matti , Kinnula Vuokko L. , Mannermaa Arto , Soini Ylermi
Published: April 2023

Abstract
NRF2 activates several protective genes, such as sulfiredoxin (SRXN1), as a response to oxidative and xenobiotic stress. Defects in NRF2 pathway may increase cancer susceptibility. In tumor cells, activation of NRF2 may lead to chemo- and radioresistance and thus affect patient outcome. Nine single-nucleotide polymorphisms on NRF2 gene and eight on SRXN1 were genotyped in 452 patients with breast cancer and 370 controls. Protein expression of NRF2 and SRXN1 was studied in 373 breast carcinomas by immunohistochemistry. Statistical significance of the associations between genotypes, protein expression, clinicopathologic variables, and survival was assessed. A high level (>25%) of cytoplasmic NRF2 positivity was observed in 237 of 361 (66%) and SRXN1 positivity was observed in 82 of 363 (23%) cases. The NRF2 rs6721961 genotype TT was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350–16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491–3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002–3.478). The NRF2 rs2886162 allele A was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162–3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047–2.748). The NRF2 rs1962142 T allele was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042). The NRF2 rs2706110 AA genotype was associated with an increased risk of breast cancer, and the SRXN1 rs6053666 C allele was associated with a decrease in breast cancer risk (P = 0.011 and 0.017). NRF2 and SRXN1 genetic polymorphisms are associated with breast cancer risk and survival, implicating that mechanisms associated with reactive oxygen species and NRF2 pathway are involved in breast cancer initiation and progression. Cancer Res; 72(21); 5537–46. ©2012 AACR.
Data from RNAi-Mediated Targeting of Noncoding and Coding Sequences in DNA Repair Gene Messages Efficiently Radiosensitizes Human Tumor Cells
Authors: Zheng Zhiming , Ng Wooi Loon , Zhang Xiangming , Olson Jeffrey J. , Hao Chunhai , Curran Walter J. , Wang Ya
Published: April 2023

Abstract
Human tumor cell death during radiotherapy is caused mainly by ionizing radiation (IR)–induced DNA double-strand breaks (DSB), which are repaired by either homologous recombination repair (HRR) or nonhomologous end-joining (NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize tumor cells to IR, this approach is limited by inefficiencies of gene silencing. In this study, we show that combining an artificial miRNA (amiR) engineered to target 3′-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ factor) along with an siRNA to target the gene coding region can improve silencing efficiencies to achieve more robust radiosensitization than a single approach alone. Mechanistically, the combinatorial knockdown decreased targeted gene expression through both a reduction in mRNA stability and a blockade to mRNA translation. Together, our findings establish a general method of gene silencing that is more efficient and particularly suited for suppressing genes that are difficult to downregulate by amiR- or siRNA-based methods alone. Cancer Res; 72(5); 1221–8. ©2012 AACR.
Data from β1 Integrin Targeting Potentiates Antiangiogenic Therapy and Inhibits the Growth of Bevacizumab-Resistant Glioblastoma
Authors: Carbonell W. Shawn , DeLay Michael , Jahangiri Arman , Park Catherine C. , Aghi Manish K.
Published: April 2023

Abstract
Antiangiogenic therapies like bevacizumab offer promise for cancer treatment, but acquired resistance, which often includes an aggressive mesenchymal phenotype, can limit the use of these agents. Upregulation of β1 integrin (ITGB1) occurs in some bevacizumab-resistant glioblastomas (BRG) whereby, mediating tumor–microenvironment interactions, we hypothesized that it may mediate a mesenchymal-type resistance to antiangiogenic therapy. Immunostaining analyses of β1 integrin and its downstream effector kinase FAK revealed upregulation in 75% and 86% of BRGs, respectively, compared with pretreatment paired specimens. Furthermore, flow cytometry revealed eight-fold more β1 integrin in primary BRG cells compared with cells from bevacizumab-naïve glioblastomas (BNG). Fluorescence recovery after photobleaching of cells engineered to express a β1-GFP fusion protein indicated that the mobile β1 integrin fraction was doubled, and half-life of β1 integrin turnover in focal adhesions was reduced markedly in BRG cells compared with bevacizumab-responsive glioblastoma multiforme cells. Hypoxia, which was increased with acquisition of bevacizumab resistance, was associated with increased β1 integrin expression in cultured BNG cells. BRGs displayed an aggressive mesenchymal-like phenotype in vitro. We found that growth of BRG xenograft tumors was attenuated by the β1 antibody, OS2966, allowing a 20-fold dose reduction of bevacizumab per cycle in this model. Intracranial delivery of OS2966 through osmotic pumps over 28 days increased tumor cell apoptosis, decreased tumor cell invasiveness, and blunted the mesenchymal morphology of tumor cells. We concluded that β1 integrin upregulation in BRGs likely reflects an onset of hypoxia caused by antiangiogenic therapy, and that β1 inhibition is well tolerated in vivo as a tractable strategy to disrupt resistance to this therapy. Cancer Res; 73(10); 3145–54. ©2013 AACR.
Data from DNA Methylation Does Not Stably Lock Gene Expression but Instead Serves as a Molecular Mark for Gene Silencing Memory
Authors: Raynal Noël J.-M. , Si Jiali , Taby Rodolphe F. , Gharibyan Vazganush , Ahmed Saira , Jelinek Jaroslav , Estécio Marcos R.H. , Issa Jean-Pierre J.
Published: April 2023

Abstract
DNA methylation is commonly thought of as a “molecular lock” that leads to permanent gene silencing. To investigate this notion, we tested 24 different histone deacetylase inhibitors (HDACi) on colon cancer cells that harbor a GFP locus stably integrated and silenced by a hypermethylated cytomegalovirus (CMV) promoter. We found that HDACi efficiently reactivated expression of GFP and many other endogenous genes silenced by DNA hypermethylation. After treatment, all promoters were marked with active chromatin, yet DNA hypermethylation did not change. Thus, DNA methylation could not prevent gene reactivation by drug-induced resetting of the chromatin state. In evaluating the relative contribution of DNA methylation and histone modifications to stable gene silencing, we followed expression levels of GFP and other genes silenced by DNA hypermethylation over time after treatment with HDACi or DNA-demethylating drugs. Reactivation of methylated loci by HDACi was detectable for only 2 weeks, whereas DNA-demethylating drugs induced permanent epigenetic reprogramming. Therefore, DNA methylation cannot be considered as a lock for gene expression but rather as a memory signal for long-term maintenance of gene silencing. These findings define chromatin as an important druggable target for cancer epigenetic therapy and suggest that removal of DNA methylation signals is required to achieve long-term gene reactivation. Cancer Res; 72(5); 1170–81. ©2012 AACR.
Data from Dmp1 Physically Interacts with p53 and Positively Regulates p53′s Stability, Nuclear Localization, and Function
Authors: Frazier Donna P. , Kendig Robert D. , Kai Fumitake , Maglic Dejan , Sugiyama Takayuki , Morgan Rachel L. , Fry Elizabeth A. , Lagedrost Sarah J. , Sui Guangchao , Inoue Kazushi
Published: April 2023

Abstract
The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell-cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here, we report findings supporting this concept with the definition of an Arf-independent function for Dmp1 in tumor suppression. We found that Dmp1 and p53 can interact directly in mammalian cells via the carboxyl-terminus of p53 and the DNA-binding domain of Dmp1. Expression of Dmp1 antagonized ubiquitination of p53 by Mdm2 and promoted nuclear localization of p53. Dmp1–p53 binding significantly increased the level of p53, independent of the DNA-binding activity of Dmp1. Mechanistically, p53 target genes were activated synergistically by the coexpression of Dmp1 and p53 in p53−/−;Arf−/− cells, and genotoxic responses of these genes were hampered more dramatically in Dmp1−/− and p53−/− cells than in Arf−/− cells. Together, our findings identify a robust new mechanism of p53 activation mediated by direct physical interaction between Dmp1 and p53. Cancer Res; 72(7); 1740–50. ©2012 AACR.
Data from Elevation of Receptor Tyrosine Kinases by Small Molecule AKT Inhibitors in Prostate Cancer Is Mediated by Pim-1
Authors: Cen Bo , Mahajan Sandeep , Wang Wenxue , Kraft Andrew S.
Published: April 2023

Abstract
The PI3K/AKT pathway is hyperactivated in prostate cancer but its effective therapeutic targeting has proven difficult. In particular, the antitumor activity of AKT inhibitors is attenuated by upregulation of receptor tyrosine kinases (RTK) through an uncharacterized feedback mechanism. In this report, we show that RNA interference-mediated silencing or pharmacologic inhibition of Pim-1 activity curtails AKT inhibitor-induced upregulation of RTKs in prostate cancer cells. Although Pim kinases have been implicated in cap-dependent translational control, we find that in the context of AKT inhibition, the expression of RTKs is controlled by Pim-1 in a cap-independent manner by controlling internal ribosome entry. Combination of Pim and AKT inhibitors resulted in synergistic inhibition of prostate tumor growth in vitro and in vivo. Together, our results show that Pim-1 mediates resistance to AKT inhibition and suggest its targeting to improve the efficacy of AKT inhibitors in anticancer therapy. Cancer Res; 73(11); 3402–11. ©2013 AACR.
Data from β-Arrestin-1 Mediates Nicotine-Induced Metastasis through E2F1 Target Genes That Modulate Epithelial–Mesenchymal Transition
Authors: Pillai Smitha , Trevino Jose , Rawal Bhupendra , Singh Sandeep , Kovacs Michelle , Li Xueli , Schell Michael , Haura Eric , Bepler Gerold , Chellappan Srikumar
Published: April 2023

Abstract
Cigarette smoking is a major risk factor in the development of non–small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC. Cancer Res; 75(6); 1009–20. ©2015 AACR.
Data from Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage
Authors: Wu Wenwen , Nishikawa Hiroyuki , Fukuda Takayo , Vittal Vinayak , Asano Masahide , Miyoshi Yasuo , Klevit Rachel E. , Ohta Tomohiko
Published: April 2023

Abstract
Stable retention of BRCA1/BARD1 complexes at sites of DNA damage is required for the proper response to DNA double-strand breaks (DSB). Here, we demonstrate that the BRCT domain of BARD1 is crucial for its retention through interaction with HP1. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent but RNF168-independent manner. This interaction is mediated primarily by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacted with the chromoshadow domain of HP1 in vitro. Mutations in this motif (or simultaneous depletion of all three HP1 isoforms) disrupted retention of BARD1, BRCA1, and CtIP at DSB sites and allowed ectopic accumulation of RIF1, an effector of nonhomologous end-joining, at damaged loci in S-phase. UNC0638, a small-molecule inhibitor of histone lysine methyltransferase (HKMT), abolished retention and cooperated with the PARP inhibitor olaparib to block cancer cell growth. Taken together, our findings show how BARD1 promotes retention of the BRCA1/BARD1 complex at damaged DNA sites and suggest the use of HKMT inhibitors to leverage the application of PARP inhibitors to treat breast cancer. Cancer Res; 75(7); 1311–21. ©2015 AACR.
Data from IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis
Authors: Chen Chong , Cao Fengqi , Bai Lipeng , Liu Yan , Xie Junling , Wang Wei , Si Qin , Yang Jian , Chang Antao , Liu Dong , Liu Dachuan , Chuang Tsung-Hsien , Xiang Rong , Luo Yunping
Published: April 2023

Abstract
Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKβ) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKβ, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAi-mediated silencing of LIN28B or pharmacologic inhibition of IKKβ was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers. Cancer Res; 75(8); 1725–35. ©2015 AACR.
Data from Identification of Novel Fusion Genes in Testicular Germ Cell Tumors
Authors: Hoff Andreas M. , Alagaratnam Sharmini , Zhao Sen , Bruun Jarle , Andrews Peter W. , Lothe Ragnhild A. , Skotheim Rolf I.
Published: April 2023

Abstract
Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their nonmalignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression. Cancer Res; 76(1); 108–16. ©2015 AACR.
Data from Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells
Authors: Bodogai Monica , Moritoh Kanako , Lee-Chang Catalina , Hollander Christine M. , Sherman-Baust Cheryl A. , Wersto Robert P. , Araki Yoshihiko , Miyoshi Ichiro , Yang Li , Trinchieri Giorgio , Biragyn Arya
Published: April 2023

Abstract
Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBreg) can block metastasis despite MDSC expansion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations that expand in cancer have only partially primed regulatory function and limited prometastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying, in part, on TgfβR1/TgfβR2 signaling. MDSC fully educated in this manner exhibit an increased production of reactive oxygen species and NO and more efficiently suppress CD4+ and CD8+ T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfβR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are important regulators of the immunosuppressive and prometastatic functions of MDSC. Cancer Res; 75(17); 3456–65. ©2015 AACR.
Data from Single-Strand DNA-Binding Protein SSB1 Facilitates TERT Recruitment to Telomeres and Maintains Telomere G-Overhangs
Authors: Pandita Raj K. , Chow Tracy T. , Udayakumar Durga , Bain Amanda L. , Cubeddu Liza , Hunt Clayton R. , Shi Wei , Horikoshi Nobuo , Zhao Yong , Wright Woodring E. , Khanna Kum Kum , Shay Jerry W. , Pandita Tej K.
Published: April 2023

Abstract
Proliferating mammalian stem and cancer cells express telomerase [telomerase reverse transcriptase (TERT)] in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA-binding protein SSB1, which has a critical role in DNA double-strand break (DSB) repair. Here, we report that SSB1 binds specifically to G-strand telomeric DNA in vitro and associates with telomeres in vivo. SSB1 interacts with the TERT catalytic subunit and regulates its interaction with telomeres. Deletion of SSB1 reduces TERT interaction with telomeres and leads to G-overhang loss. Although SSB1 is recruited to DSB sites, we found no corresponding change in TERT levels at these sites, implying that SSB1–TERT interaction relies upon a specific chromatin structure or context. Our findings offer an explanation for how telomerase is recruited to telomeres to facilitate G-strand DNA extension, a critical step in maintaining telomere ends and cell viability in all cancer cells. Cancer Res; 75(5); 858–69. ©2015 AACR.
Data from Reprogramming of the ERRα and ERα Target Gene Landscape Triggers Tamoxifen Resistance in Breast Cancer
Authors: Thewes Verena , Simon Ronald , Schroeter Petra , Schlotter Magdalena , Anzeneder Tobias , Büttner Reinhard , Benes Vladimir , Sauter Guido , Burwinkel Barbara , Nicholson Robert I. , Sinn Hans-Peter , Schneeweiss Andreas , Deuschle Ulrich , Zapatka Marc , Heck Stefanie , Lichter Peter
Published: April 2023

Abstract
Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer. Cancer Res; 75(4); 720–31. ©2015 AACR.
Data from Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice
Authors: Huang Jenny Li-Ying , Urtatiz Oscar , Van Raamsdonk Catherine D.
Published: April 2023

Abstract
GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQQ209L under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQQ209L to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQQ209L expression in human tumors. Intriguingly, enforced expression of GNAQQ209L progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQQ209 mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQQ209L mutations contribute to both the initiation and metastatic progression of uveal melanoma. Cancer Res; 75(16); 3384–97. ©2015 AACR.
Data from Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity
Authors: Shanker Anil , Pellom Samuel T. , Dudimah Duafalia F. , Thounaojam Menaka C. , de Kluyver Rachel L. , Brooks Alan D. , Yagita Hideo , McVicar Daniel W. , Murphy William J. , Longo Dan L. , Sayers Thomas J.
Published: April 2023

Abstract
Cancer immunotherapy shows great promise but many patients fail to show objective responses, including in cancers that can respond well, such as melanoma and renal adenocarcinoma. The proteasome inhibitor bortezomib sensitizes solid tumors to apoptosis in response to TNF-family death ligands. Because T cells provide multiple death ligands at the tumor site, we investigated the effects of bortezomib on T-cell responses in immunotherapy models involving low-avidity antigens. Bortezomib did not affect lymphocyte or tissue-resident CD11c+CD8+ dendritic cell counts in tumor-bearing mice, did not inhibit dendritic cell expression of costimulatory molecules, and did not decrease MHC class I/II-associated antigen presentation to cognate T cells. Rather, bortezomib activated NF-κB p65 in CD8+ T cells, stabilizing expression of T-cell receptor CD3ζ and IL2 receptor-α, while maintaining IFNγ secretion to improve FasL-mediated tumor lysis. Notably, bortezomib increased tumor cell surface expression of Fas in mice as well as human melanoma tissue from a responsive patient. In renal tumor-bearing immunodeficient Rag2−/− mice, bortezomib treatment after adoptive T-cell immunotherapy reduced lung metastases and enhanced host survival. Our findings highlight the potential of proteasome inhibitors to enhance antitumor T-cell function in the context of cancer immunotherapy. Cancer Res; 75(24); 5260–72. ©2015 AACR.
Data from Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation
Authors: Lin Dandan , Lei Lei , Liu Yonghao , Zhang Yinsheng , Hu Bo , Bao Guangming , Song Yuan , Jin Ziqi , Liu Chunliang , Mei Yu , Sandikin Dedy , Wu Yan , Zhao Lixiang , Yu Xiao , Liu Haiyan
Published: April 2023

Abstract
Hepatocellular carcinoma is a worldwide health problem with limited treatment options and poor prognosis. Inflammation associated with liver injury and hepatocyte regeneration can lead to fibrosis, cirrhosis, and eventually, hepatocellular carcinoma. IL1α is one of the most important inflammatory cytokines involved in inflammation and tumor development. IL1α presents as multiple forms in vivo, including precursor, propiece, membrane, and secreted forms, and their functions have been thought to be different. The role of membrane IL1α in hepatocellular carcinoma tumorigenesis is still not clear. Here, we examined the functions of membrane IL1α in murine hepatocellular carcinoma models. We found that membrane IL1α potently inhibited hepatocellular carcinoma tumor growth. Further studies showed that membrane IL1α promoted T- and natural killer (NK)–cell activation in vivo. IFNγ production by CD8+ T and NK cells was also increased as a result of membrane IL1α expression. Moreover, the cytotoxicity of the CTL and NK cells was also enhanced by membrane IL1α expression. Furthermore, in vitro studies demonstrated that membrane IL1α could directly activate T cells and NK cells in a cell contact–dependent manner. Conversely, depletion of both CD8+ T and NK cells suppressed the antitumor activity of membrane IL1α. Our studies demonstrated that membrane IL1α could promote antitumor immune responses through activation of T and NK cells. Thus, our findings provide new insights of IL1α functions during hepatocellular carcinoma development. Cancer Res; 76(11); 3179–88. ©2016 AACR.
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: April 2023

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 Glioblastomas Require Integrin αvβ3/PAK4 Signaling to Escape Senescence
Authors: Franovic Aleksandra , Elliott Kathryn C. , Seguin Laetitia , Camargo M. Fernanda , Weis Sara M. , Cheresh David A.
Published: April 2023

Abstract
Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvβ3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvβ3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvβ3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvβ3–PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer. Cancer Res; 75(21); 4466–73. ©2015 AACR.
Data from Aldehyde Dehydrogenase Is Regulated by β-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells
Authors: Cojoc Monica , Peitzsch Claudia , Kurth Ina , Trautmann Franziska , Kunz-Schughart Leoni A. , Telegeev Gennady D. , Stakhovsky Eduard A. , Walker John R. , Simin Karl , Lyle Stephen , Fuessel Susanne , Erdmann Kati , Wirth Manfred P. , Krause Mechthild , Baumann Michael , Dubrovska Anna
Published: April 2023

Abstract
Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial–mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH+ and ALDH− cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/β-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of β-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH+ tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH+ cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy. Cancer Res; 75(7); 1482–94. ©2015 AACR.
Data from Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer
Authors: Espelin Christopher W. , Leonard Shannon C. , Geretti Elena , Wickham Thomas J. , Hendriks Bart S.
Published: April 2023

Abstract
Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial. Cancer Res; 76(6); 1517–27. ©2016 AACR.
Data from GPCR Signaling Mediates Tumor Metastasis via PI3Kβ
Authors: Khalil Bassem D. , Hsueh Christine , Cao Yanyan , Abi Saab Widian F. , Wang Yarong , Condeelis John S. , Bresnick Anne R. , Backer Jonathan M.
Published: April 2023

Abstract
Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kβ has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein–coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease. Cancer Res; 76(10); 2944–53. ©2016 AACR.
Data from MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell–Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages
Authors: Yamada Kazuya , Uchiyama Akihiko , Uehara Akihito , Perera Buddhini , Ogino Sachiko , Yokoyama Yoko , Takeuchi Yuko , Udey Mark C. , Ishikawa Osamu , Motegi Sei-ichiro
Published: April 2023

Abstract
Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow–derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects coimplanted with KO-MSC compared with WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays, we confirmed that WT-MSC–conditioned medium was more potent at inducing M2 macrophage polarization, compared with KO-MSC–conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis. Cancer Res; 76(14); 4283–92. ©2016 AACR.
Data from Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre–metastatic Niche
Authors: Giles Amber Jin , Reid Caitlin Marie , Evans Justin DeWayne , Murgai Meera , Vicioso Yorleny , Highfill Steven Lorenz , Kasai Miki , Vahdat Linda , Mackall Crystal Lee , Lyden David , Wexler Leonard , Kaplan Rosandra Natasha
Published: April 2023

Abstract
Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPC) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells in early metastatic sites of tumor-bearing mice. The number of CD11b+Ly6g+ cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacologic mobilization of HSPCs increased metastasis, whereas depletion of Gr1+ cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation. Cancer Res; 76(6); 1335–47. ©2015 AACR.
Data from CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation
Authors: Liu Yuan , Amin Elianna B. , Mayo Marty W. , Chudgar Neel P. , Bucciarelli Peter R. , Kadota Kyuichi , Adusumilli Prasad S. , Jones David R.
Published: April 2023

Abstract
Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non–small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ϵ–mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome–induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of S30 in BRMS1 or the use of the CK2-specific small-molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2α' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease-free survival. Collectively, we identify a therapeutically exploitable posttranslational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer. Cancer Res; 76(9); 2675–86. ©2016 AACR.