bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from HAVCR/KIM-1 Activates the IL-6/STAT-3 Pathway in Clear Cell Renal Cell Carcinoma and Determines Tumor Progression and Patient Outcome
Authors: Cuadros Thaïs , Trilla Enric , Sarró Eduard , Vilà Maya R. , Vilardell Jordi , de Torres Inés , Salcedo Mayte , López-Hellin Joan , Sánchez Alex , Ramón y Cajal Santiago , Itarte Emilio , Morote Juan , Meseguer Anna
Published: March 2023

Abstract
Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1–related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC. Cancer Res; 74(5); 1416–28. ©2014 AACR.
Data from Mechanisms of Resistance to Intermittent Androgen Deprivation in Patients with Prostate Cancer Identified by a Novel Computational Method
Authors: Morken Jason D. , Packer Aaron , Everett Rebecca A. , Nagy John D. , Kuang Yang
Published: March 2023

Abstract
For progressive prostate cancer, intermittent androgen deprivation (IAD) is one of the most common and effective treatments. Although this treatment is usually initially effective at regressing tumors, most patients eventually develop castration-resistant prostate cancer (CRPC), for which there is no effective treatment and is generally fatal. Although several biologic mechanisms leading to CRPC development and their relative frequencies have been identified, it is difficult to determine which mechanisms of resistance are developing in a given patient. Personalized therapy that identifies and targets specific mechanisms of resistance developing in individual patients is likely one of the most promising methods of future cancer therapy. Prostate-specific antigen (PSA) is a biomarker for monitoring tumor progression. We incorporated a cell death rate (CDR) function into a previous dynamical PSA model that was highly accurate at fitting clinical PSA data for 7 patients. The mechanism of action of IAD is largely induction of apoptosis, and each mechanism of resistance varies in its CDR dynamics. Thus, we analyze the CDR levels and their time-dependent oscillations to identify mechanisms of resistance to IAD developing in individual patients. Cancer Res; 74(14); 3673–83. ©2014 AACR.
Data from MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence
Authors: Tabor Vedrana , Bocci Matteo , Alikhani Nyosha , Kuiper Raoul , Larsson Lars-Gunnar
Published: March 2023

Abstract
The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence, a major barrier imposed on tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether MYC has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen-regulatable MycER, we show that tamoxifen-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose-dependent manner, resulting in reduced survival. Furthermore, MYC activation leads to reduced expression of the senescence markers p16INK4A, p21CIP1, and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by tamoxifen withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1, and reduced number of Ki67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process, with implications for future treatment strategies. Cancer Res; 74(16); 4222–9. ©2014 AACR.
Data from Activated ERBB2/HER2 Licenses Sensitivity to Apoptosis upon Endoplasmic Reticulum Stress through a PERK-Dependent Pathway
Authors: Martín-Pérez Rosa , Palacios Carmen , Yerbes Rosario , Cano-González Ana , Iglesias-Serret Daniel , Gil Joan , Reginato Mauricio J. , López-Rivas Abelardo
Published: March 2023

Abstract
HER2/Neu/ERBB2 is a receptor tyrosine kinase overexpressed in approximately 20% of human breast tumors. Truncated or mutant isoforms that show increased oncogenicity compared with the wild-type receptor are found in many breast tumors. Here, we report that constitutively active ERBB2 sensitizes human breast epithelial cells to agents that induce endoplasmic reticulum stress, altering the unfolded protein response (UPR) of these cells. Deregulation of the ERK, AKT, and mTOR activities elicited by mutant ERBB2 was involved in mediating this differential UPR response, elevating the response to endoplasmic reticulum stress, and apoptotic cell death. Mechanistic investigations revealed that the increased sensitivity of mutant ERBB2-expressing cells to endoplasmic reticulum stress relied upon a UPR effector signaling involving the PERK–ATF4–CHOP pathway, upregulation of the proapoptotic cell surface receptor TRAIL-R2, and activation of proapoptotic caspase-8. Collectively, our results offer a rationale for the therapeutic exploration of treatments inducing endoplasmic reticulum stress against mutant ERBB2-expressing breast tumor cells. Cancer Res; 74(6); 1766–77. ©2014 AACR.
Data from Histone Chaperone CHAF1A Inhibits Differentiation and Promotes Aggressive Neuroblastoma
Authors: Barbieri Eveline , De Preter Katleen , Capasso Mario , Chen Zaowen , Hsu Danielle M. , Tonini Gian Paolo , Lefever Steve , Hicks John , Versteeg Rogier , Pession Andrea , Speleman Frank , Kim Eugene S. , Shohet Jason M.
Published: March 2023

Abstract
Neuroblastoma arises from the embryonal neural crest secondary to a block in differentiation. Long-term patient survival correlates inversely with the extent of differentiation, and treatment with retinoic acid or other prodifferentiation agents improves survival modestly. In this study, we show the histone chaperone and epigenetic regulator CHAF1A functions in maintaining the highly dedifferentiated state of this aggressive malignancy. CHAF1A is a subunit of the chromatin modifier chromatin assembly factor 1 and it regulates H3K9 trimethylation of key target genes regulating proliferation, survival, and differentiation. Elevated CHAF1A expression strongly correlated with poor prognosis. Conversely, CHAF1A loss-of-function was sufficient to drive neuronal differentiation in vitro and in vivo. Transcriptome analysis of cells lacking CHAF1A revealed repression of oncogenic signaling pathways and a normalization of glycolytic metabolism. Our findings demonstrate that CHAF1A restricts neural crest differentiation and contributes to the pathogenesis of high-risk neuroblastoma. Cancer Res; 74(3); 765–74. ©2013 AACR.
Data from A Preclinical Model of CD38-Pretargeted Radioimmunotherapy for Plasma Cell Malignancies
Authors: Green Damian J. , Orgun Nural N. , Jones Jon C. , Hylarides Mark D. , Pagel John M. , Hamlin Donald K. , Wilbur D.S. , Lin Yukang , Fisher Darrell R. , Kenoyer Aimee L. , Frayo Shani L. , Gopal Ajay K. , Orozco Johnnie J. , Gooley Theodore A. , Wood Brent L. , Bensinger William I. , Press Oliver W.
Published: March 2023

Abstract
The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin–biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals. Cancer Res; 74(4); 1179–89. ©2013 AACR.
Data from Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood–Brain Barrier
Authors: Huang Yujie , Hoffman Caitlin , Rajappa Prajwal , Kim Joon-Hyung , Hu Wenhuo , Huse Jason , Tang Zhongshu , Li Xuri , Weksler Babette , Bromberg Jacqueline , Lyden David C. , Greenfield Jeffrey P.
Published: March 2023

Abstract
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)–expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain. Cancer Res; 74(4); 1011–21. ©2013 AACR.
Data from IGF-I Regulates Redox Status in Breast Cancer Cells by Activating the Amino Acid Transport Molecule xC−
Authors: Yang Yuzhe , Yee Douglas
Published: March 2023

Abstract
Insulin-like growth factors (IGF) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC−, which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER+) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacologic inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the type I IGF receptor (IGF-IR) in a manner reversed by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER+ breast cancer cells by regulating xC− transporter function to protect cancer cells from ROS in an IRS-1–dependent manner. Our findings suggest that inhibiting xC− transporter function may synergize with modalities that target the IGF-IR to heighten their therapeutic effects. Cancer Res; 74(8); 2295–305. ©2014 AACR.
Data from NOTCH3 Signaling Regulates MUSASHI-1 Expression in Metastatic Colorectal Cancer Cells
Authors: Pastò Anna , Serafin Valentina , Pilotto Giorgia , Lago Claudia , Bellio Chiara , Trusolino Livio , Bertotti Andrea , Hoey Timothy , Plateroti Michelina , Esposito Giovanni , Pinazza Marica , Agostini Marco , Nitti Donato , Amadori Alberto , Indraccolo Stefano
Published: March 2023

Abstract
MUSASHI-1 (MSI-1) is a well-established stem cell marker in both normal and malignant colon cells and it acts by positively regulating the NOTCH pathway through inactivation of NUMB, a NOTCH signaling repressor. To date, the mechanisms of regulation of MSI-1 levels remain largely unknown. Here, we investigated the regulation of MSI-1 by NOTCH signaling in colorectal cancer cell lines and in primary cultures of colorectal cancer metastases. Stimulation by the NOTCH ligand DLL4 was associated with an increase of MSI-1 mRNA and protein levels, and this phenomenon was prevented by the addition of an antibody neutralizing NOTCH2/3 but not NOTCH1. Moreover, forced expression of activated NOTCH3 increased MSI-1 levels, whereas silencing of NOTCH3 by short hairpin RNA reduced MSI-1 levels in both colorectal cancer cells and CRC tumor xenografts. Consistent with these findings, enforced NOTCH3 expression or stimulation by DLL4 increased levels of activated NOTCH1 in colorectal cell lines. Finally, treatment of colorectal cancer cells with anti-NOTCH2/3 antibody increased NUMB protein while significantly reducing formation of tumor cell spheroids. This novel feed-forward circuit involving DLL4, NOTCH3, MSI-1, NUMB, and NOTCH1 may be relevant for regulation of NOTCH signaling in physiologic processes as well as in tumor development. With regard to therapeutic implications, NOTCH3-specific drugs could represent a valuable strategy to limit NOTCH signaling in the context of colorectal cancers overexpressing this receptor. Cancer Res; 74(7); 2106–18. ©2014 AACR.
Data from Cancer-Associated Mutations in Healthy Individuals: Assessing the Risk of Carcinogenesis
Authors: Rodriguez-Brenes Ignacio A. , Komarova Natalia L. , Wodarz Dominik
Published: March 2023

Abstract
Mutations associated with hematopoietic malignancies have been repeatedly identified in healthy individuals. For certain cases, such as the t(14;18) translocation and monoclonal B-cell lymphocytosis, no clear link between the presence of aberrant cells and the later development of cancer has been established. Intriguingly, longitudinal studies suggest that these abnormalities persist for long periods of time in some individuals, but in others are transient in which they disappear completely. Here, we present a mathematical model, based on cellular replication limits, that provides a possible explanation for these seemingly contradictory findings. It proposes that the transient and persistent nature of the phenotypes depends on the stage in the differentiation pathway of a given lineage in which the mutation originates. Our work suggests that cellular replication limits may not only prevent cancer by aborting clonal expansion of cells, but also by influencing the fate of altered but nonneoplastic cells in healthy tissue. Cancer Res; 74(6); 1661–9. ©2014 AACR.
Data from Strict Requirement for Vector-Induced Type I Interferon in Efficacious Antitumor Responses to Virally Encoded IL12
Authors: Melero Ignacio , Quetglas Jose I. , Reboredo Mercedes , Dubrot Juan , Rodriguez-Madoz Juan R. , Mancheño Uxua , Casales Erkuden , Riezu-Boj Jose I. , Ruiz-Guillen Marta , Ochoa Maria C. , Sanmamed Miguel F. , Thieblemont Nathalie , Smerdou Cristian , Hervas-Stubbs Sandra
Published: March 2023

Abstract
Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding IL12 (SFV-IL12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFNβ transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFNβ signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN-I production. Macrophages, plasmacytoid, and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor (IFNAR) abolished the therapeutic activity of SFV-IL12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL12 expression, because IFNAR-deficient mice expressed the viral IL12 transgene even more strongly than wild-type (WT) hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, although tumor-specific CD8 T lymphocytes expanded robustly after intratumoral injection of WT mice with SFV-IL12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research. Cancer Res; 75(3); 497–507. ©2014 AACR.
Data from Intratumoral Modeling of Gefitinib Pharmacokinetics and Pharmacodynamics in an Orthotopic Mouse Model of Glioblastoma
Authors: Sharma Jyoti , Lv Hua , Gallo James M.
Published: March 2023

Abstract
Like many solid tumors, glioblastomas are characterized by intratumoral biologic heterogeneity that may contribute to a variable distribution of drugs and their associated pharmacodynamic responses, such that the standard pharmacokinetic approaches based on analysis of whole-tumor homogenates may be inaccurate. To address this aspect of tumor pharmacology, we analyzed intratumoral pharmacokinetic/pharmacodynamic characteristics of the EGFR inhibitor gefitinib in mice with intracerebral tumors and developed corresponding mathematical models. Following a single oral dose of gefitinib (50 or 150 mg/kg), tumors were processed at selected times according to a novel brain tumor sectioning protocol that generated serial samples to measure gefitinib concentrations, phosphorylated extracellular signal-regulated kinase (pERK), and immunohistochemistry in 4 different regions of tumors. Notably, we observed up to 3-fold variations in intratumoral concentrations of gefitinib, but only up to half this variability in pERK levels. As we observed a similar degree of variation in the immunohistochemical index termed the microvessel pericyte index (MPI), a measure of permeability in the blood–brain barrier, we used MPI in a hybrid physiologically-based pharmacokinetic (PBPK) model to account for regional changes in drug distribution that were observed. Subsequently, the PBPK models were linked to a pharmacodynamic model that could account for the variability observed in pERK levels. Together, our tumor sectioning protocol enabled integration of the intratumoral pharmacokinetic/pharmacodynamic variability of gefitinib and immunohistochemical indices followed by the construction of a predictive PBPK/pharmacodynamic model. These types of models offer a mechanistic basis to understand tumor heterogeneity as it impacts the activity of anticancer drugs. Cancer Res; 73(16); 5242–52. ©2013 AACR.
Data from Reprogramming the Chromatin Landscape: Interplay of the Estrogen and Glucocorticoid Receptors at the Genomic Level
Authors: Miranda Tina B. , Voss Ty C. , Sung Myong-Hee , Baek Songjoon , John Sam , Hawkins Mary , Grøntved Lars , Schiltz R. Louis , Hager Gordon L.
Published: March 2023

Abstract
Cross-talk between estrogen receptors (ER) and glucocorticoid receptors (GR) has been shown to contribute to the development and progression of breast cancer. Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease. However, mechanistic details defining the cellular interactions between ER and GR are poorly understood. We investigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER and GR. Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements. Binding to these newly accessible sites occurs either by direct recognition of ER response elements or indirectly through interactions with other factors. The unveiling of this mechanism is important for understanding cellular interactions between ER and GR and may represent a general mechanism for cross-talk between nuclear receptors in human disease. Cancer Res; 73(16); 5130–9. ©2013 AACR.
Data from microRNA-148a Is a Prognostic oncomiR That Targets MIG6 and BIM to Regulate EGFR and Apoptosis in Glioblastoma
Authors: Kim Jungeun , Zhang Ying , Skalski Michael , Hayes Josie , Kefas Benjamin , Schiff David , Purow Benjamin , Parsons Sarah , Lawler Sean , Abounader Roger
Published: March 2023

Abstract
Great interest persists in useful prognostic and therapeutic targets in glioblastoma. In this study, we report the definition of miRNA (miR)-148a as a novel prognostic oncomiR in glioblastoma. miR-148a expression was elevated in human glioblastoma specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels were a risk indicator for glioblastoma patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. Two direct targets of miR-148a were identified, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM, which rescue experiments showed were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR-148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy. Cancer Res; 74(5); 1541–53. ©2014 AACR.
Data from Expression of Variant Isoforms of the Tyrosine Kinase SYK Determines the Prognosis of Hepatocellular Carcinoma
Authors: Hong Jian , Yuan Yunfei , Wang Jianping , Liao Yadi , Zou Ruhai , Zhu Chuanlong , Li Binkui , Liang Yi , Huang Pinzhu , Wang Zongwei , Lin Wenyu , Zeng Yixin , Le Dai Jia , Chung Raymond T.
Published: March 2023

Abstract
The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal–regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L+/S−) tumors exhibited longer overall survival and time to recurrence than those with SYK(L−/S−) or SYK(L+/S+) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention. Cancer Res; 74(6); 1845–56. ©2014 AACR.
Data from CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110
Authors: Hu Shanhu , Danilov Alexey V. , Godek Kristina , Orr Bernardo , Tafe Laura J. , Rodriguez-Canales Jaime , Behrens Carmen , Mino Barbara , Moran Cesar A. , Memoli Vincent A. , Mustachio Lisa Maria , Galimberti Fabrizio , Ravi Saranya , DeCastro Andrew , Lu Yun , Sekula David , Andrew Angeline S. , Wistuba Ignacio I. , Freemantle Sarah , Compton Duane A. , Dmitrovsky Ethan
Published: March 2023

Abstract
Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced anaphase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor–mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition–driven anaphase catastrophe. Independent examination of murine and human paired normal–malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations. Cancer Res; 75(10); 2029–38. ©2015 AACR.
Data from Lack of p53 Augments Antitumor Functions in Cytolytic T Cells
Authors: Banerjee Anirban , Thyagarajan Krishnamurthy , Chatterjee Shilpak , Chakraborty Paramita , Kesarwani Pravin , Soloshchenko Myroslawa , Al-Hommrani Mazen , Andrijauskaite Kristina , Moxley Kelly , Janakiraman Harinarayanan , Scheffel Matthew J. , Helke Kristi , Armenson Kent , Palanisamy Viswanathan , Rubinstein Mark P. , Mayer Elizabeth-Garrett , Cole David J. , Paulos Chrystal M. , Voelkel-Johnson Christina , Nishimura Michael I. , Mehrotra Shikhar
Published: March 2023

Abstract
Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor–mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope–reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229–40. ©2016 AACR.
Data from Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
Authors: Busch Susann , Sims Andrew H. , Stål Olle , Fernö Mårten , Landberg Göran
Published: March 2023

Abstract
One third of the patients with estrogen receptor α (ERα)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ERα and TGFβ signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFβ signaling. In this study, we analyzed TGFβ receptor type 2 (TGFBR2) expression and correlated it with ERα status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ERα-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERα phosphorylation, tamoxifen-induced transcriptional activation of TGFβ, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGFβ signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERα-positive forms of this disease. Cancer Res; 75(7); 1457–69. ©2015 AACR.
Data from Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells
Authors: Cheng Chun-Ting , Kuo Ching-Ying , Ouyang Ching , Li Chien-Feng , Chung Yiyin , Chan David C. , Kung Hsing-Jien , Ann David K.
Published: March 2023

Abstract
Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress. Cancer Res; 76(17); 5006–18. ©2016 AACR.
Data from The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia
Authors: Baker Adele , Gregory Gareth P. , Verbrugge Inge , Kats Lev , Hilton Joshua J. , Vidacs Eva , Lee Erwin M. , Lock Richard B. , Zuber Johannes , Shortt Jake , Johnstone Ricky W.
Published: March 2023

Abstract
Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9–driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9–driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. Cancer Res; 76(5); 1158–69. ©2015 AACR.
Data from Neuropilin-2 Regulates Endosome Maturation and EGFR Trafficking to Support Cancer Cell Pathobiology
Authors: Dutta Samikshan , Roy Sohini , Polavaram Navatha S. , Stanton Marissa J. , Zhang Heyu , Bhola Tanvi , Hönscheid Pia , Donohue Terrence M. , Band Hamid , Batra Surinder K. , Muders Michael H. , Datta Kaustubh
Published: March 2023

Abstract
Neuropilin-2 (NRP2) is a non-tyrosine kinase receptor frequently overexpressed in various malignancies, where it has been implicated in promoting many protumorigenic behaviors, such as imparting therapeutic resistance to metastatic cancer cells. Here, we report a novel function of NRP2 as a regulator of endocytosis, which is enhanced in cancer cells and is often associated with increased metastatic potential and drug resistance. We found that NRP2 depletion in human prostate and pancreatic cancer cells resulted in the accumulation of EEA1/Rab5-positive early endosomes concomitant with a decrease in Rab7-positive late endosomes, suggesting a delay in early-to-late endosome maturation. NRP2 depletion also impaired the endocytic transport of cell surface EGFR, arresting functionally active EGFR in endocytic vesicles that consequently led to aberrant ERK activation and cell death. Mechanistic investigations revealed that WD-repeat– and FYVE-domain–containing protein 1 (WDFY1) functioned downstream of NRP2 to promote endosome maturation, thereby influencing the endosomal trafficking of EGFR and the formation of autolysosomes responsible for the degradation of internalized cargo. Overall, our results indicate that the NRP2/WDFY1 axis is required for maintaining endocytic activity in cancer cells, which supports their oncogenic activities and confers drug resistance. Therefore, therapeutically targeting endocytosis may represent an attractive strategy to selectively target cancer cells in multiple malignancies. Cancer Res; 76(2); 418–28. ©2015 AACR.
Data from Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth
Authors: Argyros Orestis , Karampelas Theodoros , Asvos Xenophon , Varela Aimilia , Sayyad Nisar , Papakyriakou Athanasios , Davos Constantinos H. , Tzakos Andreas G. , Fokas Demosthenes , Tamvakopoulos Constantin
Published: March 2023

Abstract
The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R–expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide–drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation. Cancer Res; 76(5); 1181–92. ©2015 AACR.
Data from Quantitative Phosphotyrosine Profiling of Patient-Derived Xenografts Identifies Therapeutic Targets in Pediatric Leukemia
Authors: Dolai Sibasish , Sia Keith C.S. , Robbins Alissa K. , Zhong Ling , Heatley Sue L. , Vincent Tiffaney L. , Hochgräfe Falko , Sutton Rosemary , Kurmasheva Raushan T. , Revesz Tamas , White Deborah L. , Houghton Peter J. , Smith Malcolm A. , Teachey David T. , Daly Roger J. , Raftery Mark J. , Lock Richard B.
Published: March 2023

Abstract
Activating mutations in tyrosine kinases (TK) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with “spike-in” stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B- or T-cell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient samples. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia. Cancer Res; 76(9); 2766–77. ©2016 AACR.
Data from An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis
Authors: Suyama Kimita , Yao Jiahong , Liang Huizhi , Benard Outhiriaradjou , Loudig Olivier D. , Amgalan Dulguun , McKimpson Wendy M. , Phillips Greg R. , Segall Jeffrey , Wang Yihong , Fineberg Susan , Norton Larry , Kitsis Richard N. , Hazan Rachel B.
Published: March 2023

Abstract
The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/−S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple-negative breast cancer cells, specific ablation of Akt3/−S472 enhanced, whereas overexpression, suppressed mammary tumor growth, consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting, as opposed to suppressing, apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.

Significance: These results illuminate an unexpected function for an endogenously expressed Akt isoform in promoting apoptosis, underscoring the likelihood that different Akt isoforms exert distinct functions in human cancer. Cancer Res; 78(1); 103–14. ©2017 AACR.
Data from Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase
Authors: Weygant Nathaniel , Ge Yang , Qu Dongfeng , Kaddis John S. , Berry William L. , May Randal , Chandrakesan Parthasarathy , Bannerman-Menson Edwin , Vega Kenneth J. , Tomasek James J. , Bronze Michael S. , An Guangyu , Houchen Courtney W.
Published: March 2023

Abstract
Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem–like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem–like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan–Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem–like cells in these malignancies. Cancer Res; 76(14); 4090–9. ©2016 AACR.
Data from FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes
Authors: Kang Jengmin , Shin Seung-Hyun , Yoon Haejin , Huh June , Shin Hyun-Woo , Chun Yang-Sook , Park Jong-Wan
Published: March 2023

Abstract
The prolyl hydroxylase domain-containing proteins (PHD1-3) and the asparaginyl hydroxlyase factor inhibiting HIF (FIH) are oxygen sensors for hypoxia-inducible factor-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here, we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis.

Significance: These findings deepen understanding of oxygen-dependent gene regulation and cancer metastasis in response to hypoxia. Cancer Res; 78(5); 1184–99. ©2017 AACR.