bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma
Authors: Liu Xinran , Zhou Yafan , Liu Xinyuan , Peng Anlin , Gong Hao , Huang Lizi , Ji Kaige , Petersen Robert B. , Zheng Ling , Huang Kun
Published: March 2024

Abstract
MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC. Cancer Res; 74(22); 6623–34. ©2014 AACR.
Data from Nuclear Factor of Activated T-cell Activity Is Associated with Metastatic Capacity in Colon Cancer
Authors: Tripathi Manish K. , Deane Natasha G. , Zhu Jing , An Hanbing , Mima Shinji , Wang Xiaojing , Padmanabhan Sekhar , Shi Zhiao , Prodduturi Naresh , Ciombor Kristen K. , Chen Xi , Washington M. Kay , Zhang Bing , Beauchamp R. Daniel
Published: March 2024

Abstract
Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis-related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence. Cancer Res; 74(23); 6947–57. ©2014 AACR.
Data from Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors
Authors: Nishio Nobuhiro , Diaconu Iulia , Liu Hao , Cerullo Vincenzo , Caruana Ignazio , Hoyos Valentina , Bouchier-Hayes Lisa , Savoldo Barbara , Dotti Gianpietro
Published: March 2024

Abstract
The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195–205. ©2014 AACR.
Data from Ubiquitin-like Protein FAT10 Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Modifying β-Catenin Degradation
Authors: Yuan Rongfa , Wang Kai , Hu Junwen , Yan Chen , Li Ming , Yu Xin , Liu Xiuxia , Lei Jun , Guo Wuhua , Wu Linquan , Hong Kui , Shao Jianghua
Published: March 2024

Abstract
The ubiquitin-like protein FAT10 and the homeobox protein HOXB9 each promote metastatic progression in hepatocellular carcinoma (HCC). In this study, we investigated the clinicopathologic significance of FAT10 and HOXB9 in HCC and investigated a mechanistic role for FAT10 in HOXB9-mediated invasiveness and metastasis. Relative to adjacent normal tissues, FAT10 and HOXB9 were markedly overexpressed in HCC, where a positive correlation in their expression and associated malignant characteristics were found. RNAi-mediated silencing of FAT10 decreased HOXB9 expression and inhibited HCC invasion and metastasis in vitro and in vivo. The effects of FAT10 silencing were reversed by HOXB9 overexpression, whereas RNAi-mediated silencing of HOXB9 decreased HCC invasion and metastasis driven by FAT10 overexpression. Mechanistically, FAT10 regulated HOXB9 expression by modulating the β-catenin/TCF4 pathway, directly binding to β-catenin and preventing its ubiquitination and degradation. Together, our results identified a novel HCC regulatory circuit involving FAT10, β-catenin/TCF4, and HOXB9, the dysfunction of which drives invasive and metastatic character in HCC. Cancer Res; 74(18); 5287–300. ©2014 AACR.
Data from SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression
Authors: Wang Shaomeng , Sun Wei , Zhao Yujun , McEachern Donna , Meaux Isabelle , Barrière Cédric , Stuckey Jeanne A. , Meagher Jennifer L. , Bai Longchuan , Liu Liu , Hoffman-Luca Cassandra Gianna , Lu Jianfeng , Shangary Sanjeev , Yu Shanghai , Bernard Denzil , Aguilar Angelo , Dos-Santos Odette , Besret Laurent , Guerif Stéphane , Pannier Pascal , Gorge-Bernat Dimitri , Debussche Laurent
Published: March 2024

Abstract
Blocking the oncoprotein murine double minute 2 (MDM2)–p53 protein–protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2–p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with Ki = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53–MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53. Cancer Res; 74(20); 5855–65. ©2014 AACR.
Data from Targeting the c-Met/FZD8 Signaling Axis Eliminates Patient-Derived Cancer Stem–like Cells in Head and Neck Squamous Carcinomas
Authors: Sun Shuyang , Liu Suling , Duan Sheng Zhong , Zhang Lei , Zhou Henghua , Hu Yongjie , Zhou Xianghui , Shi Chaoji , Zhou Rong , Zhang Zhiyuan
Published: March 2024

Abstract
Cancer stem–like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment. Cancer Res; 74(24); 7546–59. ©2014 AACR.
Data from DUSP1 Phosphatase Regulates the Proinflammatory Milieu in Head and Neck Squamous Cell Carcinoma
Authors: Zhang Xiaoyi , Hyer J. Madison , Yu Hong , D'Silva Nisha J. , Kirkwood Keith L.
Published: March 2024

Abstract
DUSP1 is a dual-specificity phosphatase that regulates mitogen-activated protein (MAP) kinase activity. Studies have associated loss of DUSP1 expression with certain cancers, but there has been no report of a mechanism by which this supports tumor progression. In this study, we found DUSP1 mRNA and protein decreased in human head and neck squamous cell carcinoma tissues compared with adjacent nontumor controls. To evaluate the impact of this difference, we compared the susceptibility of Dusp1-deficient mice with oral squamous carcinogenesis induced by 4-nitroquinoline 1-oxide. Dusp1-deficient mice displayed enhanced disease progression, characterized by advanced onset, histologic stage, and tumor burden. In a syngeneic model of tumor progression, subcutaneous injection of EO771 cells formed faster-growing tumors in Dusp1-deficient mice, an effect abrogated by inhibition of p38 MAP kinase with SB203580. Histologic and quantitative assessments demonstrated increased inflammation and deregulated chemokine and cytokine expression in Dusp1-deficient tumor tissues. Specifically, proinflammatory cytokine IL1β was elevated. IL1β production was recapitulated ex vivo in primary bone marrow–derived macrophages from Dusp1-deficient mice. Together, our results clearly establish the role of Dusp1 as a tumor suppressor gene that regulates cancer-associated inflammation. Cancer Res; 74(24); 7191–7. ©2014 AACR.
Data from Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade
Authors: Zhao Yu , Li Hang , Zhang Yingyi , Li Leilei , Fang Runping , Li Yinghui , Liu Qian , Zhang Weiying , Qiu Liyan , Liu Fabao , Zhang Xiaodong , Ye Lihong
Published: March 2024

Abstract
Abnormal lipid metabolism is a hallmark of tumorigenesis. Accumulating evidence demonstrates that fatty acid synthase (FAS, FASN) is a metabolic oncogene that supports the growth and survival of tumor cells and is highly expressed in many cancers. Here, we report that the oncoprotein, hepatitis B X-interacting protein (HBXIP, LAMTOR5) contributes to abnormal lipid metabolism. We show that high expression of HBXIP in 236 breast cancer patients was significantly associated with decreased overall survival and progression-free survival. Interestingly, the expression of HBXIP was positively related to that of FAS in clinical breast cancer tissues, and HBXIP overexpression in breast cancer cells resulted in FAS upregulation. Mechanistically, HBXIP upregulated SREBP-1c (SREBF1), which activates the transcription of FAS, by directly interacting with and coactivating nuclear receptor (NR) liver X receptors (LXR). Physiologically, LXRs are activated via a coactivator containing NR motif in a ligand-dependent manner. However, in breast cancer cells, HBXIP containing the corepressor/nuclear receptor motif with special flanking sequence could coactivate LXRs independent of ligand. Moreover, overexpressed SREBP-1c was able to activate the transcription of HBXIP, forming a positive-feedback loop. Functionally, HBXIP enhanced lipogenesis, resulting in the growth of breast cancer cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP contributes to the abnormal lipid metabolism in breast cancer through LXRs/SREBP-1c/FAS signaling, providing new insights into the mechanisms by which cancer cells reprogram lipid metabolism in their favor. Cancer Res; 76(16); 4696–707. ©2016 AACR.
Data from The Polyamine Catabolic Enzyme SAT1 Modulates Tumorigenesis and Radiation Response in GBM
Authors: Brett-Morris Adina , Wright Bradley M. , Seo Yuji , Pasupuleti Vinay , Zhang Junran , Lu Jun , Spina Raffaella , Bar Eli E. , Gujrati Maneesh , Schur Rebecca , Lu Zheng-Rong , Welford Scott M.
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. To understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes in which inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2–M and S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biologic significance of elevated SAT1 expression in GBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies. Cancer Res; 74(23); 6925–34. ©2014 AACR.
Data from High Expression of CAI2, a 9p21-Embedded Long Noncoding RNA, Contributes to Advanced-Stage Neuroblastoma
Authors: Barnhill Lisa M. , Williams Richard T. , Cohen Olga , Kim Youngjin , Batova Ayse , Mielke Jenna A. , Messer Karen , Pu Minya , Bao Lei , Yu Alice L. , Diccianni Mitchell B.
Published: March 2024

Abstract
Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon γ in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high-risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease. Cancer Res; 74(14); 3753–63. ©2014 AACR.
Data from LASP1 Is a HIF1α Target Gene Critical for Metastasis of Pancreatic Cancer
Authors: Zhao Tiansuo , Ren He , Li Jing , Chen Jing , Zhang Huan , Xin Wen , Sun Yan , Sun Lei , Yang Yongwei , Sun Junwei , Wang Xiuchao , Gao Song , Huang Chongbiao , Zhang Huafeng , Yang Shengyu , Hao Jihui
Published: March 2024

Abstract
LASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here, we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC. Cancer Res; 75(1); 111–9. ©2014 AACR.
Data from A Systematic Analysis Reveals Heterogeneous Changes in the Endocytic Activities of Cancer Cells
Authors: Elkin Sarah R. , Bendris Nawal , Reis Carlos R. , Zhou Yunyun , Xie Yang , Huffman Kenneth E. , Minna John D. , Schmid Sandra L.
Published: March 2024

Abstract
Metastasis is a multistep process requiring cancer cell signaling, invasion, migration, survival, and proliferation. These processes require dynamic modulation of cell surface proteins by endocytosis. Given this functional connection, it has been suggested that endocytosis is dysregulated in cancer. To test this, we developed In-Cell ELISA assays to measure three different endocytic pathways: clathrin-mediated endocytosis, caveolae-mediated endocytosis, and clathrin-independent endocytosis and compared these activities using two different syngeneic models for normal and oncogene-transformed human lung epithelial cells. We found that all endocytic activities were reduced in the transformed versus normal counterparts. However, when we screened 29 independently isolated non–small cell lung cancer (NSCLC) cell lines to determine whether these changes were systematic, we observed significant heterogeneity. Nonetheless, using hierarchical clustering based on their combined endocytic properties, we identified two phenotypically distinct clusters of NSCLCs. One co-clustered with mutations in KRAS, a mesenchymal phenotype, increased invasion through collagen and decreased growth in soft agar, whereas the second was enriched in cells with an epithelial phenotype. Interestingly, the two clusters also differed significantly in clathrin-independent internalization and surface expression of CD44 and CD59. Taken together, our results suggest that endocytotic alterations in cancer cells that affect cell surface expression of critical molecules have a significant influence on cancer-relevant phenotypes, with potential implications for interventions to control cancer by modulating endocytic dynamics. Cancer Res; 75(21); 4640–50. ©2015 AACR.
Data from PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy
Authors: Hsieh Chen-Lin , Botta Ginevra , Gao Shuai , Li Tiantian , Van Allen Eliezer M. , Treacy Daniel J. , Cai Changmeng , He Housheng Hansen , Sweeney Christopher J. , Brown Myles , Balk Steven P. , Nelson Peter S. , Garraway Levi A. , Kantoff Philip W.
Published: March 2024

Abstract
Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. Cancer Res; 75(10); 1944–8. ©2015 AACR.
Data from STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells
Authors: Yang Heng , Yamazaki Takahiro , Pietrocola Federico , Zhou Heng , Zitvogel Laurence , Ma Yuting , Kroemer Guido
Published: March 2024

Abstract
STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3−/− cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell–dependent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3−/− cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3−/− cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3−/− and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. Cancer Res; 75(18); 3812–22. ©2015 AACR.
Data from Targeting the miR-221–222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma
Authors: Zhao Jian-Jun , Chu Zhang-Bo , Hu Yu , Lin Jianhong , Wang Zhongqiu , Jiang Meng , Chen Ming , Wang Xujun , Kang Yue , Zhou Yangsheng , Chonghaile Triona Ni , Johncilla Melanie E. , Tai Yu-Tzu , Cheng Jin Q. , Letai Antony , Munshi Nikhil C. , Anderson Kenneth C. , Carrasco Ruben D.
Published: March 2024

Abstract
Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221–222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221–222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221–222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR-221–222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221–222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221–222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221–222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221–222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221–222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221–222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221–222 in drug resistance and provides a rationale for the targeting of miR-221–222 as a means of improving patient outcomes. Cancer Res; 75(20); 4384–97. ©2015 AACR.
Data from TUBB3/βIII-Tubulin Acts through the PTEN/AKT Signaling Axis to Promote Tumorigenesis and Anoikis Resistance in Non–Small Cell Lung Cancer
Authors: McCarroll Joshua A. , Gan Pei Pei , Erlich Rafael B. , Liu Marjorie , Dwarte Tanya , Sagnella Sharon S. , Akerfeldt Mia C. , Yang Lu , Parker Amelia L. , Chang Melissa H. , Shum Michael S. , Byrne Frances L. , Kavallaris Maria
Published: March 2024

Abstract
βIII-tubulin (encoded by TUBB3) expression is associated with therapeutic resistance and aggressive disease in non–small cell lung cancer (NSCLC), but the basis for its pathogenic influence is not understood. Functional and differential proteomics revealed that βIII-tubulin regulates expression of proteins associated with malignant growth and metastases. In particular, the adhesion-associated tumor suppressor maspin was differentially regulated by βIII-tubulin. Functionally, βIII-tubulin suppression altered cell morphology, reduced tumor spheroid outgrowth, and increased sensitivity to anoikis. Mechanistically, the PTEN/AKT signaling axis was defined as a critical pathway regulated by βIII-tubulin in NSCLC cells. βIII-Tubulin blockage in vivo reduced tumor incidence and growth. Overall, our findings revealed how βIII-tubulin influences tumor growth in NSCLC, defining new biologic functions and mechanism of action of βIII-tubulin in tumorigenesis. Cancer Res; 75(2); 415–25. ©2014 AACR.
Data from TUSC4 Functions as a Tumor Suppressor by Regulating BRCA1 Stability
Authors: Peng Yang , Dai Hui , Wang Edward , Lin Curtis Chun-Jen , Mo Wei , Peng Guang , Lin Shiaw-Yih
Published: March 2024

Abstract
BRCA1 expression is lost frequently in breast cancers in which it promotes malignant development. In the present study, we performed a global expression analysis of breast cancer cells in which the tumor-suppressor candidate gene TUSC4 was silenced to gain insights into its function. TUSC4 silencing affected genes involved in cell cycle and cell death, which have broad reaching influence on cancer development. Most importantly, we found a cluster pattern of gene-expression profiles in TUSC4-silenced cells that defined a homologous recombination (HR) repair defect signature. Mechanistic investigations indicated that TUSC4 protein could physically interact with the E3 ligase Herc2, which prevents BRCA1 degradation through the ubiquitination pathway. TUSC4 silencing enhanced BRCA1 polyubiquitination, leading to its degradation and a marked reduction in HR repair efficiency. Notably, ectopic expression of TUSC4 suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, TUSC4 silencing was sufficient to transform normal mammary epithelial cells and to enhance sensitivity to PARP inhibitors. Our results provide a set of genetic and biologic proofs that TUSC4 functions as a bona fide tumor suppressor by regulating the protein stability and function of BRCA1 in breast cancer. Cancer Res; 75(2); 378–86. ©2014 AACR.
Data from Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells
Authors: Vilgelm Anna E. , Pawlikowski Jeff S. , Liu Yan , Hawkins Oriana E. , Davis Tyler A. , Smith Jessica , Weller Kevin P. , Horton Linda W. , McClain Colt M. , Ayers Gregory D. , Turner David C. , Essaka David C. , Stewart Clinton F. , Sosman Jeffrey A. , Kelley Mark C. , Ecsedy Jeffrey A. , Johnston Jeffrey N. , Richmond Ann
Published: March 2024

Abstract
Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends. Cancer Res; 75(1); 181–93. ©2014 AACR.
Data from Differentiation and Loss of Malignant Character of Spontaneous Pulmonary Metastases in Patient-Derived Breast Cancer Models
Authors: Bockhorn Jessica , Prat Aleix , Chang Ya-Fang , Liu Xia , Huang Simo , Shang Meng , Nwachukwu Chika , Gomez-Vega Maria J. , Harrell J. Chuck , Olopade Olufunmilayo I. , Perou Charles M. , Liu Huiping
Published: March 2024

Abstract
Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)–derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met–derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial–mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype. Cancer Res; 74(24); 7406–17. ©2014 AACR.
Data from YAP Promotes Malignant Progression of Lkb1-Deficient Lung Adenocarcinoma through Downstream Regulation of Survivin
Authors: Zhang Wenjing , Gao Yijun , Li Fuming , Tong Xinyuan , Ren Yan , Han Xiangkun , Yao Shun , Long Fei , Yang Zhongzhou , Fan Hengyu , Zhang Lei , Ji Hongbin
Published: March 2024

Abstract
The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non–small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the KrasG12D lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient KrasG12D mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC. Cancer Res; 75(21); 4450–7. ©2015 AACR.
Data from Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation
Authors: Veliça Pedro , Zech Mathias , Henson Sian , Holler Angelika , Manzo Teresa , Pike Rebecca , Santos e Sousa Pedro , Zhang Lei , Schiedlmeier Bernhard , Pule Martin , Stauss Hans , Chakraverty Ronjon
Published: March 2024

Abstract
A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1low T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions. Cancer Res; 75(13); 2641–52. ©2015 AACR.
Data from Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
Authors: Cedervall Jessica , Zhang Yanyu , Huang Hua , Zhang Lei , Femel Julia , Dimberg Anna , Olsson Anna-Karin
Published: March 2024

Abstract
Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet–neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1β, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites. Cancer Res; 75(13); 2653–62. ©2015 AACR.
Data from Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline
Authors: Quinn Bridget A. , Dash Rupesh , Sarkar Siddik , Azab Belal , Bhoopathi Praveen , Das Swadesh K. , Emdad Luni , Wei Jun , Pellecchia Maurizio , Sarkar Devanand , Fisher Paul B.
Published: March 2024

Abstract
Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. Cancer Res; 75(11); 2305–15. ©2015 AACR.
Data from KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer
Authors: Simó-Riudalbas Laia , Pérez-Salvia Montserrat , Setien Fernando , Villanueva Alberto , Moutinho Catia , Martínez-Cardús Anna , Moran Sebastian , Berdasco Maria , Gomez Antonio , Vidal Enrique , Soler Marta , Heyn Holger , Vaquero Alejandro , de la Torre Carolina , Barceló-Batllori Silvia , Vidal August , Roz Luca , Pastorino Ugo , Szakszon Katalin , Borck Guntram , Moura Conceição S. , Carneiro Fátima , Zondervan Ilse , Savola Suvi , Iwakawa Reika , Kohno Takashi , Yokota Jun , Esteller Manel
Published: March 2024

Abstract
Recent efforts to sequence human cancer genomes have highlighted that point mutations in genes involved in the epigenetic setting occur in tumor cells. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis, where little is known about the genetic events related to its development. Herein, we have identified the presence of homozygous deletions of the candidate histone acetyltransferase KAT6B, and the loss of the corresponding transcript, in SCLC cell lines and primary tumors. Furthermore, we show, in vitro and in vivo, that the depletion of KAT6B expression enhances cancer growth, while its restoration induces tumor suppressor–like features. Most importantly, we demonstrate that KAT6B exerts its tumor-inhibitory role through a newly defined type of histone H3 Lys23 acetyltransferase activity. Cancer Res; 75(18); 3936–45. ©2015 AACR.
Data from Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice
Authors: Liu Xiaojun , Jiang Shuguang , Fang Chongyun , Yang Shiyu , Olalere Devvora , Pequignot Edward C. , Cogdill Alexandria P. , Li Na , Ramones Melissa , Granda Brian , Zhou Li , Loew Andreas , Young Regina M. , June Carl H. , Zhao Yangbing
Published: March 2024

Abstract
Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissues that express it at physiologic levels. A CAR-expressing T-cell panel was generated with target antigen affinities varying over three orders of magnitude. High-affinity cells recognized target expressed at any level, including at levels in normal cells that were undetectable by flow cytometry. Affinity-tuned cells exhibited robust antitumor efficacy similar to high-affinity cells, but spared normal cells expressing physiologic target levels. The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach. Cancer Res; 75(17); 3596–607. ©2015 AACR.
Data from Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB
Authors: Zeng Zhiping , Sun Zhe , Huang Mingfeng , Zhang Weidong , Liu Jie , Chen Liqun , Chen Fan , Zhou Yuqi , Lin Jiacheng , Huang Fengyu , Xu Lin , Zhuang Zixing , Guo Shangjie , Alitongbieke Gulimiran , Xie Guobin , Xu Yang , Lin Bingzhen , Cao Xihua , Su Ying , Zhang Xiao-kun , Zhou Hu
Published: March 2024

Abstract
Retinoid X receptor alpha (RXRα) and its N-terminally truncated version, tRXRα, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFα/NFκB signaling pathway in a tRXRα-dependent manner. tRXRα promotes TNFα-induced NF-κB activation through its interaction with TRAF2 and enhances TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NF-κB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action. Cancer Res; 75(10); 2049–60. ©2015 AACR.
Data from Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma
Authors: Soroceanu Liliana , Matlaf Lisa , Khan Sabeena , Akhavan Armin , Singer Eric , Bezrookove Vladimir , Decker Stacy , Ghanny Saleena , Hadaczek Piotr , Bengtsson Henrik , Ohlfest John , Luciani-Torres Maria-Gloria , Harkins Lualhati , Perry Arie , Guo Hong , Soteropoulos Patricia , Cobbs Charles S.
Published: March 2024

Abstract
Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate-early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with oncogenic properties. Here, we show how HCMV IEs are preferentially expressed in glioma stem–like cells (GSC), where they colocalize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSCs that are endogenously infected with HCMV, attenuating IE expression by an RNAi-based strategy was sufficient to inhibit tumorsphere formation, Sox2 expression, cell-cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSCs elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSCs, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and proinflammatory cytokines, resembling the therapeutically resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miR-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSCs infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared with mock-infected human GSCs. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in GBM cells. Cancer Res; 75(15); 3065–76. ©2015 AACR.