bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PAI-1 Leads to G1-Phase Cell-Cycle Progression through Cyclin D3/cdk4/6 Upregulation
Authors: Giacoia Evan Gomes , Miyake Makito , Lawton Adrienne , Goodison Steve , Rosser Charles J.
Published: March 2024

Abstract
The canonical function of plasminogen activator inhibitor-1 (PAI-1/SERPINE1) is as an inhibitor of urokinase-type plasminogen activator for blood clot maintenance, but it is now also considered a pleiotropic factor that can exert diverse cellular and tumorigenic effects. However, the mechanism controlling its pleiotropic effects is far from being understood. To elucidate the tumorigenic role of PAI-1, we tested the effects of PAI-1 after manipulation of its expression or through the use of a small-molecule inhibitor, tiplaxtinin. Downregulation of PAI-1 significantly reduced cellular proliferation through an inability to progress from the G0–G1 phase of the cell cycle. Accordingly, overexpression of PAI-1 augmented proliferation by encouraging S-phase entry. Biochemically, cell-cycle arrest was associated with the depletion of the G1-phase transition complexes, cyclin D3/cdk4/6 and cyclin E/cdk2, in parallel with the upregulation of the cell-cycle inhibitors p53, p21Cip1/Waf1, and p27Kip1. PAI-1 depletion significantly decreased the tumor size of urothelial T24 and UM-UC-14 xenografts, and overexpression of PAI-1 substantially increased the tumor size of HeLa xenografts. Finally, immunohistochemical analysis of human bladder and cervical tumor tissue microarrays revealed increased expression of PAI-1 in cancerous tissue, specifically in aggressive tumors, supporting the relevance of this molecule in human tumor biology.

Implications: Targeting PAI-1 has beneficial antitumoral effects and should be further investigated clinically. Mol Cancer Res; 12(3); 322–34. ©2014 AACR.
Data from A Novel EGFR Extracellular Domain Mutant, EGFRΔ768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma
Authors: Keller James , Nimnual Anjaruwee S. , Varghese Mathew S. , VanHeyst Kristen A. , Hayman Michael J. , Chan Edward L.
Published: March 2024

Abstract
EGFR is a popular therapeutic target for many cancers. EGFR inhibitors have been tested in children with refractory neuroblastoma. Interestingly, partial response or stable disease was observed in a few neuroblastoma patients. As EGFR mutations are biomarkers for response to anti-EGFR drugs, primary neuroblastoma tumors and cell lines were screened for mutations. A novel EGFR extracellular domain deletion mutant, EGFRΔ768, was discovered and the biologic and biochemical properties of this mutant were characterized and compared with wild-type and EGFRvIII receptors. EGFRΔ768 was found to be constitutively active and localized to the cell surface. Its expression conferred resistance to etoposide and drove proliferation as well as invasion of cancer cells. While EGFRΔ768 had similarity to EGFRvIII, its biologic and biochemical properties were distinctly different from both the EGFRvIII and wild-type receptors. Even though erlotinib inhibited EGFRΔ768, its effect on the mutant was not as strong as that on wild-type EGFR and EGFRvIII. In addition, downstream signaling of EGFRΔ768 was different from that of the wild-type receptor. In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFRΔ768. The EGFRΔ768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant.

Implications: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740–52. ©2016 AACR.
Data from Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer
Authors: Eke Iris , Makinde Adeola Y. , Aryankalayil Molykutty J. , Reedy Jessica L. , Citrin Deborah E. , Chopra Sunita , Ahmed Mansoor M. , Coleman C. Norman
Published: March 2024

Abstract
Adaptation of tumor cells to radiotherapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted 2 months later. Integrins are transmembrane cell adhesion molecules that are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2–10 Gy) or a multifractionated regimen (2–10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (ITGB1 and ITGB4) were upregulated after radiation in vitro and in vivo. This overexpression lasted for more than 2 months and was dose dependent. Moreover, radiation-induced upregulation of β1 and β4 integrin resulted in significantly increased tumor cell death after treatment with inhibitory antibodies. Combined, these findings indicate that long-term tumor adaptation to radiation can result in an increased susceptibility of surviving cancer cells to molecular targeted therapy due to a radiation-induced overexpression of the target.
Implications:
Radiation induces dose- and schedule-dependent adaptive changes that are targetable for an extended time; thus suggesting radiotherapy as a unique strategy to orchestrate molecular processes, thereby providing new radiation-drug treatment options within precision cancer medicine.
Data from Bioactive Lipids, LPC and LPA, Are Novel Prometastatic Factors and Their Tissue Levels Increase in Response to Radio/Chemotherapy
Authors: Schneider Gabriela , Sellers Zachariah Payne , Abdel-Latif Ahmed , Morris Andrew J. , Ratajczak Mariusz Z.
Published: March 2024

Abstract
Bioactive lipids are fundamental mediators of a number of critical biologic processes such as inflammation, proliferation, and apoptosis. Rhabdomyosarcoma (RMS) is common in adolescence with histologic subtypes that favor metastasis. However, the factors that influence metastasis are not well appreciated. Here, it is shown that lysophosphatidylcholine (LPC) and its derivative, lysophosphatidic acid (LPA), strongly enhance motility and adhesion of human RMS cells. Importantly, these metastatic-associated phenotypes were observed at physiologic concentrations of these lipids, which naturally occur in biologic fluids. Moreover, the effects of these bioactive lipids were much stronger as compared with known peptide-based prometastatic factors in RMS, such as stromal-derived factor-1 or hepatocyte growth factor/scatter factor. Finally, both LPC and LPA levels were increased in several organs after γ-irradiation or chemotherapy, supporting the hypothesis that radio/chemotherapy induces an unwanted prometastatic environment in these organs.

Implications: LPC and LPA play a previously underappreciated role in dissemination of RMS and suggest that antimetastatic treatment with specific molecules blocking LPC/LPA activity should be part of standard radio/chemotherapy arsenal. Mol Cancer Res; 12(11); 1560–73. ©2014 AACR.
Data from Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms
Authors: Virtanen Sanna S. , Kukkonen-Macchi Anu , Vainio Minna , Elima Kati , Härkönen Pirkko L. , Jalkanen Sirpa , Yegutkin Gennady G.
Published: March 2024

Abstract
Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel- and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5′-nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin-1β (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor–dependent and –independent mechanisms.

Implications: This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes. Mol Cancer Res; 12(12); 1863–74. ©2014 AACR.
Data from p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC
Authors: Kidacki Michal , Lehman Heather L. , Green Michelle V. , Warrick Joshua I. , Stairs Douglas B.
Published: March 2024

Abstract
Despite recent improvements in treatment for head and neck squamous cell carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within 5 years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Because p120-catenin (CTNND1/P120CTN) downregulation and PIK3CA mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion. Furthermore, this study aimed to identify the key effector proteins regulated by P120CTN downregulation and PIK3CA mutations. Studies using oral keratinocytes demonstrated that P120CTN downregulation and PIK3CA mutations increased migration and invasion. In addition, P120CTN downregulation and PIK3CA mutations resulted in elevated matrix metallopeptidase 1 (MMP1) levels. Inhibition of MMP1 resulted in decreased invasion, suggesting that MMP1 plays a critical role in HNSCC invasion. Moreover, analysis of HNSCC patient specimens from The Cancer Genome Atlas confirmed these findings. Tumors with low P120CTN and PI3K pathway mutations have higher levels of MMP1 compared to tumors with high P120CTN and no PI3K pathway mutations. In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC.

Implications: Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and PIK3CA mutations. Mol Cancer Res; 15(10); 1398–409. ©2017 AACR.
Data from EZH2: Not EZHY (Easy) to Deal
Authors: Deb Gauri , Singh Anup Kumar , Gupta Sanjay
Published: March 2024

Abstract
Seminal discoveries have established that epigenetic modifications are important for driving tumor progression. Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain, by posttranslational modification of histones, the silenced state of genes involved in critical biologic processes, including cellular development, stem cell plasticity, and tumor progression. PcG proteins are found in two multimeric protein complexes called Polycomb repressive complexes: PRC1 and PRC2. Enhancer of zeste homolog 2 (EZH2), catalytic core subunit of PRC2, epigenetically silences several tumor-suppressor genes by catalyzing the trimethylation of histone H3 at lysine 27, which serves as a docking site for DNA methyltransferases and histone deacetylases. Evidence suggests that overexpression of EZH2 is strongly associated with cancer progression and poor outcome in disparate cancers, including hematologic and epithelial malignancies. The regulatory circuit and molecular cues causing EZH2 deregulation vary in different cancer types. Therefore, this review provides a comprehensive overview on the oncogenic role of EZH2 during tumorigenesis and highlights the multifaceted role of EZH2, as either a transcriptional activator or repressor depending on the cellular context. Additional insight is provided on the recent understanding of the causes and consequences of EZH2 overexpression in specific cancer types. Finally, evidence is discussed on how EZH2 has emerged as a promising target in anticancer therapy and the prospects for targeting EZH2 without affecting global methylation status. Thus, a better understanding of the complex epigenetic regulatory network controlling EZH2 expression and target genes facilitates the design of novel therapeutic interventions. Mol Cancer Res; 12(5); 639–53. ©2014 AACR.
Data from Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis
Authors: Stanford Elizabeth A. , Ramirez-Cardenas Alejandra , Wang Zhongyan , Novikov Olga , Alamoud Khalid , Koutrakis Petros , Mizgerd Joseph P. , Genco Caroline A. , Kukuruzinska Maria , Monti Stefano , Bais Manish V. , Sherr David H.
Published: March 2024

Abstract
Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo. These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.

Implications: This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro. Mol Cancer Res; 14(8); 696–706. ©2016 AACR.
Data from Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas
Authors: Laginestra Maria Antonella , Tripodo Claudio , Agostinelli Claudio , Motta Giovanna , Hartmann Sylvia , Döring Claudia , Rossi Maura , Melle Federica , Sapienza Maria Rosaria , Tabanelli Valentina , Pileri Alessandro , Fuligni Fabio , Gazzola Anna , Mannu Claudia , Sagramoso Carlo Alberto , Lonardi Silvia , Lorenzi Luisa , Bacci Francesco , Sabattini Elena , Borges Anita , Simonitsch-Klupp Ingrid , Cabecadas Jose , Campo Elias , Rosai Juan , Hansmann Martin-Leo , Facchetti Fabio , Pileri Stefano Aldo
Published: March 2024

Abstract
Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ. Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.

Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541–52. ©2017 AACR.
Data from The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma
Authors: Cheerathodi Mujeeburahiman , Avci Naze G. , Guerrero Paola A. , Tang Leung K. , Popp Julia , Morales John E. , Chen Zhihua , Carnero Amancio , Lang Frederick F. , Ballif Bryan A. , Rivera Gonzalo M. , McCarty Joseph H.
Published: March 2024

Abstract
Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment.

Implications: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma. Mol Cancer Res; 14(12); 1277–87. ©2016 AACR.
Data from Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation
Authors: Bell Jonathan B. , Eckerdt Frank , Dhruv Harshil D. , Finlay Darren , Peng Sen , Kim Seungchan , Kroczynska Barbara , Beauchamp Elspeth M. , Alley Kristen , Clymer Jessica , Goldman Stewart , Cheng Shi-Yuan , James C. David , Nakano Ichiro , Horbinski Craig , Mazar Andrew P. , Vuori Kristiina , Kumthekar Priya , Raizer Jeffrey , Berens Michael E. , Platanias Leonidas C.
Published: March 2024

Abstract
Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood–brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1–eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival.

Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32–46. ©2017 AACR.
Data from Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression
Authors: Schrecengost Randy S. , Keller Staci N. , Schiewer Matthew J. , Knudsen Karen E. , Smith Charles D.
Published: March 2024

Abstract
The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, that is, sphingosine kinase 1 and 2 (SK1 and SK2), important molecular targets for cancer drug development. ABC294640 is a first-in-class SK2 small-molecule inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer, and that sphingolipids affect signaling by both proteins, the therapeutic potential for using ABC294640 in the treatment of prostate cancer was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for prostate cancer growth and proliferation. Key findings validate that ABC294640 treatment of early-stage and advanced prostate cancer models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell-cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these pre-clinical findings support the hypotheses that SK2 activity is required for prostate cancer function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive prostate cancer.

Implications: Sphingosine kinase inhibition disrupts multiple oncogenic signaling pathways that are deregulated in prostate cancer. Mol Cancer Res; 13(12); 1591–601. ©2015 AACR.
Data from HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells
Authors: Romeo Carmella , Weber Matthew C. , Zarei Mahsa , DeCicco Danielle , Chand Saswati N. , Lobo Angie D. , Winter Jordan M. , Sawicki Janet A. , Sachs Jonathan N. , Meisner-Kober Nicole , Yeo Charles J. , Vadigepalli Rajanikanth , Tykocinski Mark L. , Brody Jonathan R.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3′-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR's role in affecting TRAIL apoptotic resistance. NanoString analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in antiapoptotic processes. Taken together, these data extend HuR's role as a key regulator of TRAIL-induced apoptosis.

Implications: Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients. Mol Cancer Res; 14(7); 599–611. ©2016 AACR.
Data from Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors
Authors: Hesson Luke B. , Ng Benedict , Zarzour Peter , Srivastava Sameer , Kwok Chau-To , Packham Deborah , Nunez Andrea C. , Beck Dominik , Ryan Regina , Dower Ashraf , Ford Caroline E. , Pimanda John E. , Sloane Mathew A. , Hawkins Nicholas J. , Bourke Michael J. , Wong Jason W.H. , Ward Robyn L.
Published: March 2024

Abstract
Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign colorectal lesions. Mutation rates in LSTs were comparable with microsatellite-stable colorectal cancers (2.4 vs. 2.6 mutations per megabase); however, copy number alterations were infrequent (averaging only 1.5 per LST). Frequent genetic, epigenetic, and transcriptional alterations were identified in genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, SLITRK5, NRXN1, ANK2). Alterations to pathways commonly mutated in colorectal cancers, namely, the p53, PI3K, and TGFβ pathways, were rare. Instead, LST-altered genes converged on axonal guidance, Wnt, and actin cytoskeleton signaling. These integrated omics data identify molecular features associated with noncancerous LSTs and highlight that mutation load, which is relatively high in LSTs, is a poor predictor of invasive potential.

Implications: The novel genetic, epigenetic, and transcriptional changes associated with LST development reveal important insights into why some adenomas do not progress to cancer. The finding that LSTs exhibit a mutational load similar to colorectal carcinomas has implications for the validity of molecular biomarkers for assessing cancer risk. Mol Cancer Res; 14(12); 1217–28. ©2016 AACR.
Data from mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis
Authors: Acquaviva Jaime , He Suqin , Sang Jim , Smith Donald L. , Sequeira Manuel , Zhang Chaohua , Bates Richard C. , Proia David A.
Published: March 2024

Abstract
Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespib-induced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

Implications: Collectively these data identify a novel strategy to optimize the therapeutic potential of HSP90 inhibitors. Mol Cancer Res; 12(5); 703–13. ©2014 AACR.
Data from Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior
Authors: Jones Brandon C. , Kelley Laura C. , Loskutov Yuriy V. , Marinak Kristina M. , Kozyreva Varvara K. , Smolkin Matthew B. , Pugacheva Elena N.
Published: March 2024

Abstract
Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility. Mechanistically, NEDD9 promotes mesenchymal migration via VAV2-dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1. In addition, NEDD9 supports a mesenchymal phenotype through stimulating polymerization of actin via promoting CTTN phosphorylation in an AURKA-dependent manner. Interestingly, an increase in RhoA activity in NEDD9-depleted cells does not facilitate a switch to functional amoeboid motility, indicating a role of NEDD9 in the regulation of downstream RhoA signaling effectors. Simultaneous depletion of NEDD9 or inhibition of AURKA in combination with inhibition of the amoeboid driver ROCK results in an additional decrease in cancer cell migration/invasion. Finally, we confirmed that a dual targeting strategy is a viable and efficient therapeutic approach to hinder the metastasis of breast cancer in xenograft models, showcasing the important need for further clinical evaluation of this regimen to impede the spread of disease and improve patient survival.

Implications: This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization. Mol Cancer Res; 15(6); 670–82. ©2017 AACR.
Data from Glucose-6–phosphatase Is a Key Metabolic Regulator of Glioblastoma Invasion
Authors: Abbadi Sara , Rodarte Julio J. , Abutaleb Ameer , Lavell Emily , Smith Chris L. , Ruff William , Schiller Jennifer , Olivi Alessandro , Levchenko Andre , Guerrero-Cazares Hugo , Quinones-Hinojosa Alfredo
Published: March 2024

Abstract
Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6–phosphatase (G6PC/G6Pase) expression is elevated in GBM when compared with normal brain. Human-derived brain tumor–initiating cells (BTIC) use this enzyme to counteract glycolytic inhibition induced by 2-deoxy-d-glucose (2DG) and sustain malignant progression. Downregulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with promalignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.

Implications: This study is the first to demonstrate a functional relationship between the critical gluconeogenic and glycogenolytic enzyme G6PC with the metabolic adaptations during GBM invasion.

Visual Overview: http://mcr.aacrjournals.org/content/12/11/1547/F1.large.jpg.

Mol Cancer Res; 12(11); 1547–59. ©2014 AACR.
Data from Dual Promoter Usage as Regulatory Mechanism of let-7c Expression in Leukemic and Solid Tumors
Authors: Pelosi Andrea , Careccia Silvia , Sagrestani Giulia , Nanni Simona , Manni Isabella , Schinzari Valeria , Martens Joost H.A. , Farsetti Antonella , Stunnenberg Hendrik G. , Gentileschi Maria Pia , Del Bufalo Donatella , De Maria Ruggero , Piaggio Giulia , Rizzo Maria Giulia
Published: March 2024

Abstract
Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)–sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.

Implications: Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878–89. ©2014 AACR.
Data from Cytoskeletal Regulatory Gene Expression and Migratory Properties of B-cell Progenitors Are Affected by the ETV6–RUNX1 Rearrangement
Authors: Palmi Chiara , Fazio Grazia , Savino Angela M. , Procter Julia , Howell Louise , Cazzaniga Valeria , Vieri Margherita , Longinotti Giulia , Brunati Ilaria , Andrè Valentina , Della Mina Pamela , Villa Antonello , Greaves Mel , Biondi Andrea , D'Amico Giovanna , Ford Anthony , Cazzaniga Giovanni
Published: March 2024

Abstract
Although the ETV6–RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6–RUNX1–positive cells during this “latency” period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6–RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6–RUNX1–expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6–RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6–RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.

Implications: Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia. Mol Cancer Res; 12(12); 1796–806. ©2014 AACR.
Data from PTEN Deficiency Mediates a Reciprocal Response to IGFI and mTOR Inhibition
Authors: Patel Mukund , Gomez Nicholas C. , McFadden Andrew W. , Moats-Staats Billie M. , Wu Sam , Rojas Andres , Sapp Travis , Simon Jeremy M. , Smith Scott V. , Kaiser-Rogers Kathleen , Davis Ian J.
Published: March 2024

Abstract
Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.

Implications: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials. Mol Cancer Res; 12(11); 1610–20. ©2014 AACR.
Data from Loss of Keratinocytic RXRα Combined with Activated CDK4 or Oncogenic NRAS Generates UVB-Induced Melanomas via Loss of p53 and PTEN in the Tumor Microenvironment
Authors: Coleman Daniel J. , Chagani Sharmeen , Hyter Stephen , Sherman Anna M. , Löhr Christiane V. , Liang Xiaobo , Ganguli-Indra Gitali , Indra Arup K.
Published: March 2024

Abstract
Understanding the molecular mechanisms behind formation of melanoma, the deadliest form of skin cancer, is crucial for improved diagnosis and treatment. One key is to better understand the cross-talk between epidermal keratinocytes and pigment-producing melanocytes. Here, using a bigenic mouse model system combining mutant oncogenic NRASQ61K (constitutively active RAS) or mutant activated CDK4R24C/R24C (prevents binding of CDK4 by kinase inhibitor p16INK4A) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRαep−/−) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRαep−/− mice are larger in size with higher proliferative capacity, and exhibit enhanced angiogenic properties and increased expression of malignant melanoma markers. Analysis of tumor adjacent normal skin from these mice revealed altered expression of several biomarkers indicative of enhanced melanoma susceptibility, including reduced expression of tumor suppressor p53 and loss of PTEN, with concomitant increase in activated AKT. Loss of epidermal RXRα in combination with UVB significantly enhances invasion of melanocytic cells to draining lymph nodes in bigenic mice expressing oncogenic NRASQ61K compared with controls with functional RXRα. These results suggest a crucial role of keratinocytic RXRα to suppress formation of UVB-induced melanomas and their progression to malignant cancers in the context of driver mutations such as activated CDK4R24C/R24C or oncogenic NRASQ61K.

Implications: These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis. Mol Cancer Res; 13(1); 186–96. ©2014 AACR.
Data from INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC
Authors: Reed Darien E. , Shokat Kevan M.
Published: March 2024

Abstract
Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4′-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concerning whether PI-3,4-P2 contributes to Akt and downstream effector activation with the known canonical signaling second messenger, phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3). If PI-3,4-P2 is a positive effector, INPP4B would be a negative regulator of PI3K signaling, and there is some evidence to support this. Utilizing phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null triple-negative breast tumor cell lines, it was unexpectedly found that silencing INPP4B decreased basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitized cells to PI3K-α and PI3K-β isoform-specific inhibitors. Conversely, overexpression of INPP4B desensitized cells to PI3K inhibitors in a phosphatase activity-dependent manner. In summary, the current investigation of INPP4B in PTEN-null TNBC suggests new mechanistic insight and the potential for targeted therapy for this aggressive subset of breast cancer.

Implications: These data support a model where PI-3,4-P2 is inhibitory toward PI3K, revealing a novel feedback mechanism under conditions of excessive signaling, and potentially an indication for PI3K-β isoform-specific inhibitors in PTEN-null TNBC that have lost INPP4B expression. Mol Cancer Res; 15(6); 765–75. ©2017 AACR.
Data from Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
Authors: Hassani Zahra , Saleh Ali , Turpault Soumaya , Khiati Salim , Morelle Willy , Vignon Jacques , Hugnot Jean-Philippe , Uro-Coste Emmanuelle , Legrand Philippe , Delaforge Marcel , Loiseau Séverine , Clarion Ludovic , Lecouvey Marc , Volle Jean-Noël , Virieux David , Pirat Jean-Luc , Duffau Hugues , Bakalara Norbert
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.