bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition
Authors: Casás-Selves Matias , Kim Jihye , Zhang Zhiyong , Helfrich Barbara A. , Gao Dexiang , Porter Christopher C. , Scarborough Hannah A. , Bunn Paul A. , Chan Daniel C. , Tan Aik Choon , DeGregori James
Published: March 2024

Abstract
Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC. Cancer Res; 72(16); 4154–64. ©2012 AACR.
Data from CCL2 Mediates Cross-talk between Cancer Cells and Stromal Fibroblasts That Regulates Breast Cancer Stem Cells
Authors: Tsuyada Akihiro , Chow Amy , Wu Jun , Somlo George , Chu Peiguo , Loera Sofia , Luu Thehang , Li Arthur Xuejun , Wu Xiwei , Ye Wei , Chen Shiuan , Zhou Weiying , Yu Yang , Wang Yuan-Zhong , Ren Xiubao , Li Hui , Scherle Peggy , Kuroki Yukio , Wang Shizhen Emily
Published: March 2024

Abstract
Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell–specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer–secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer–host communication that prompts CSC-mediated disease progression. Cancer Res; 72(11); 2768–79. ©2012 AACR.
Data from Androgen Deprivation Causes Epithelial–Mesenchymal Transition in the Prostate: Implications for Androgen-Deprivation Therapy
Authors: Sun Yuting , Wang Bu-Er , Leong Kevin G. , Yue Peng , Li Li , Jhunjhunwala Suchit , Chen Darrell , Seo Kyounghee , Modrusan Zora , Gao Wei-Qiang , Settleman Jeffrey , Johnson Leisa
Published: March 2024

Abstract
Androgen deprivation is currently a standard-of-care, first-line therapy for prostate cancer in the United States. Although this regimen effectively regresses androgen-dependent disease, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. Such castration-resistant prostate cancer represents a major clinical challenge, and the mechanisms underlying castration resistance are not fully understood. Epithelial–mesenchymal transition (EMT) is a key developmental process and has also been implicated in cancer metastasis and therapeutic resistance in recent years. However, the factors contributing to EMT in human cancers remain unclear. Here, we show that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants display an EMT as well as increased stem cell–like features following androgen deprivation. Importantly, we observed similar changes in mesenchymal features in prostate tumors from patients treated with androgen-deprivation therapy. In addition, we have delineated a feedback loop involving the androgen receptor and the Zeb1 transcription factor that seems to mediate this transition. In summary, we show for the first time that androgen deprivation induces EMT in both normal prostate and prostate cancer, revealing a potentially important consequence of a standard-of-care treatment for prostate cancer. This finding could have significant implications for second-line treatment strategies in this clinical setting. Cancer Res; 72(2); 527–36. ©2011 AACR.
Data from SIRT1 Pathway Dysregulation in the Smoke-Exposed Airway Epithelium and Lung Tumor Tissue
Authors: Beane Jennifer , Cheng Luis , Soldi Raffaella , Zhang Xiaohui , Liu Gang , Anderlind Christina , Lenburg Marc E. , Spira Avrum , Bild Andrea H.
Published: March 2024

Abstract
Cigarette smoke produces a molecular field of injury in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly upregulated in cytologically normal bronchial airway epithelial cells from active smokers compared with nonsmokers. In contrast, this activity is strikingly downregulated in non–small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and downregulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Furthermore, our findings suggest that the airway gene expression signatures derived in this study can provide novel insights into signaling pathways altered in the “field of injury” induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer. Cancer Res; 72(22); 5702–11. ©2012 AACR.
Data from RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2
Authors: Wang Hongyan , Liu Kaihua , Geng Miao , Gao Peng , Wu Xiaoyuan , Hai Yan , Li Yangxia , Li Yulong , Luo Lin , Hayes John D. , Wang Xiu Jun , Tang Xiuwen
Published: March 2024

Abstract
The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRα) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRα increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRα decreased ARE-driven gene expression. Biochemical investigations showed that RXRα interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRα bound to ARE sequences in the promoters of NRF2-regulated genes. RXRα loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRα and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non–small cell lung cancer cells where NRF2 levels are elevated, RXRα expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRα diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10); 3097–108. ©2013 AACR.
Data from RNAi-Mediated Targeting of Noncoding and Coding Sequences in DNA Repair Gene Messages Efficiently Radiosensitizes Human Tumor Cells
Authors: Zheng Zhiming , Ng Wooi Loon , Zhang Xiangming , Olson Jeffrey J. , Hao Chunhai , Curran Walter J. , Wang Ya
Published: March 2024

Abstract
Human tumor cell death during radiotherapy is caused mainly by ionizing radiation (IR)–induced DNA double-strand breaks (DSB), which are repaired by either homologous recombination repair (HRR) or nonhomologous end-joining (NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize tumor cells to IR, this approach is limited by inefficiencies of gene silencing. In this study, we show that combining an artificial miRNA (amiR) engineered to target 3′-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ factor) along with an siRNA to target the gene coding region can improve silencing efficiencies to achieve more robust radiosensitization than a single approach alone. Mechanistically, the combinatorial knockdown decreased targeted gene expression through both a reduction in mRNA stability and a blockade to mRNA translation. Together, our findings establish a general method of gene silencing that is more efficient and particularly suited for suppressing genes that are difficult to downregulate by amiR- or siRNA-based methods alone. Cancer Res; 72(5); 1221–8. ©2012 AACR.
Data from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
Authors: Tong Man , Chan Kwok Wah , Bao Jessie Y.J. , Wong Kai Yau , Chen Jin-Na , Kwan Pak Shing , Tang Kwan Ho , Fu Li , Qin Yan-Ru , Lok Si , Guan Xin-Yuan , Ma Stephanie
Published: March 2024

Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK–Raf–MEK1/2–ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024–35. ©2012 AACR.
Data from An Integrated Genomic Screen Identifies LDHB as an Essential Gene for Triple-Negative Breast Cancer
Authors: McCleland Mark L. , Adler Adam S. , Shang Yonglei , Hunsaker Thomas , Truong Tom , Peterson David , Torres Eric , Li Li , Haley Benjamin , Stephan Jean-Philippe , Belvin Marcia , Hatzivassiliou Georgia , Blackwood Elizabeth M. , Corson Laura , Evangelista Marie , Zha Jiping , Firestein Ron
Published: March 2024

Abstract
Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ER+/PR+), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all three markers (triple negative or basal-like). While targeted therapies for ER+/PR+ and HER2+ tumors have revolutionized patient treatment and increased lifespan, an urgent need exists for identifying novel targets for triple-negative breast cancers. Here, we used integrative genomic analysis to identify candidate oncogenes in triple-negative breast tumors and assess their function through loss of function screening. Using this approach, we identify lactate dehydrogenase B (LDHB), a component of glycolytic metabolism, as an essential gene in triple-negative breast cancer. Loss of LDHB abrogated cell proliferation in vitro and arrested tumor growth in fully formed tumors in vivo. We find that LDHB and other related glycolysis genes are specifically upregulated in basal-like/triple-negative breast cancers as compared with other subtypes, suggesting that these tumors are distinctly glycolytic. Consistent with this, triple-negative breast cancer cell lines were more dependent on glycolysis for growth than luminal cell lines. Finally, we find that patients with breast cancer and high LDHB expression in their tumors had a poor clinical outcome. While previous studies have focused on the ubiquitous role of LDHA in tumor metabolism and growth, our data reveal that LDHB is upregulated and required only in certain cancer genotypes. These findings suggest that targeting LDHB or other components of lactate metabolism would be of clinical benefit in triple-negative breast cancer. Cancer Res; 72(22); 5812–23. ©2012 AACR.
Data from Vaccination with Antigen-Transfected, NKT Cell Ligand–Loaded, Human Cells Elicits Robust In Situ Immune Responses by Dendritic Cells
Authors: Shimizu Kanako , Mizuno Takuya , Shinga Jun , Asakura Miki , Kakimi Kazuhiro , Ishii Yasuyuki , Masuda Kenichi , Maeda Tomoji , Sugahara Hidetoshi , Sato Yusuke , Matsushita Hirokazu , Nishida Keigo , Hanada Kenichi , Dorrie Jan , Schaft Niels , Bickham Kara , Koike Hisashi , Ando Tsuyoshi , Nagai Ryozo , Fujii Shin-ichiro
Published: March 2024

Abstract
Both innate and adaptive immunity are crucial for cancer immunosurveillance, but precise therapeutic equations to restore immunosurveillance in patients with cancer patients have yet to be developed. In murine models, α-galactosylceramide (α-GalCer)–loaded, tumor antigen–expressing syngeneic or allogeneic cells can act as cellular adjuvants, linking the innate and adaptive immune systems. In the current study, we established human artificial adjuvant vector cells (aAVC) consisting of human HEK293 embryonic kidney cells stably transfected with the natural killer T (NKT) immune cell receptor CD1d, loaded with the CD1d ligand α-GalCer and then transfected with antigen-encoding mRNA. When administered to mice or dogs, these aAVC-activated invariant NKT (iNKT) cells elicited antigen-specific T-cell responses with no adverse events. In parallel experiments, using NOD/SCID/IL-2rγcnull–immunodeficient (hDC-NOG) mouse model, we also showed that the human melanoma antigen, MART-1, expressed by mRNA transfected aAVCs can be cross-presented to antigen-specific T cells by human dendritic cells. Antigen-specific T-cell responses elicited and expanded by aAVCs were verified as functional in tumor immunity. Our results support the clinical development of aAVCs to harness innate and adaptive immunity for effective cancer immunotherapy. Cancer Res; 73(1); 62–73. ©2012 AACR.
Data from Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis
Authors: Gilkes Daniele M. , Chaturvedi Pallavi , Bajpai Saumendra , Wong Carmen C. , Wei Hong , Pitcairn Stephen , Hubbi Maimon E. , Wirtz Denis , Semenza Gregg L.
Published: March 2024

Abstract
The presence of hypoxia and fibrosis within the primary tumor are two major risk factors for metastasis of human breast cancer. In this study, we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Finally, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies and show that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer. Cancer Res; 73(11); 3285–96. ©2013 AACR.
Data from PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines
Authors: Peng Weiyi , Liu Chengwen , Xu Chunyu , Lou Yanyan , Chen Jieqing , Yang Yan , Yagita Hideo , Overwijk Willem W. , Lizée Gregory , Radvanyi Laszlo , Hwu Patrick
Published: March 2024

Abstract
Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements, many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor programmed cell death-1 (PD-1) expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. As PD-1 can attenuate T-cell–mediated antitumor responses, we tested whether its blockade with an anti–PD-1 antibody could enhance the antitumor activity of ACT in this model. Cotreatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared with treatments with either agent alone. While anti–PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow–transplant experiments using IFN-γR−/− mice implicated IFN-γ as a crucial nexus for controlling PD-1–mediated tumor infiltration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites. Cancer Res; 72(20); 5209–18. ©2012 AACR.
Data from Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases
Authors: Markant Shirley L. , Esparza Lourdes Adriana , Sun Jesse , Barton Kelly L. , McCoig Lisa M. , Grant Gerald A. , Crawford John R. , Levy Michael L. , Northcott Paul A. , Shih David , Remke Marc , Taylor Michael D. , Wechsler-Reya Robert J.
Published: March 2024

Abstract
Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH–associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2–M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15− cells and contain an increased proportion of cells in G2–M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2–M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2–M regulators may represent a novel approach for treatment of human medulloblastoma. Cancer Res; 73(20); 6310–22. ©2013 AACR.
Data from NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis
Authors: Qin Li , Wu Ye-Lin , Toneff Michael J. , Li Dabing , Liao Lan , Gao Xiuhua , Bane Fiona T. , Tien Jean C.-Y. , Xu Yixiang , Feng Zhen , Yang Zhihui , Xu Yan , Theissen Sarah M. , Li Yi , Young Leonie , Xu Jianming
Published: March 2024

Abstract
In breast cancer, overexpression of the nuclear coactivator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor-forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating breast cancer cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating colony-simulating factor 1 (CSF1) expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and breast cancer cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade, and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes breast cancer metastasis, offering a novel therapeutic target for impeding this process. Cancer Res; 74(13); 3477–88. ©2014 AACR.
Data from miR-483-5p Promotes Invasion and Metastasis of Lung Adenocarcinoma by Targeting RhoGDI1 and ALCAM
Authors: Song Qiancheng , Xu Yuanfei , Yang Cuilan , Chen Zhenguo , Jia Chunhong , Chen Juan , Zhang Yue , Lai Pinglin , Fan Xiaorong , Zhou Xuan , Lin Jun , Li Ming , Ma Wenli , Luo Shenqiu , Bai Xiaochun
Published: March 2024

Abstract
The nodal regulatory properties of microRNAs (miRNA) in metastatic cancer may offer new targets for therapeutic control. Here, we report that upregulation of miR-483-5p is correlated with the progression of human lung adenocarcinoma. miR-483-5p promotes the epithelial–mesenchymal transition (EMT) accompanied by invasive and metastatic properties of lung adenocarcinoma. Mechanistically, miR-483-5p is activated by the WNT/β-catenin signaling pathway and exerts its prometastatic function by directly targeting the Rho GDP dissociation inhibitor alpha (RhoGDI1) and activated leukocyte cell adhesion molecule (ALCAM), two putative metastasis suppressors. Furthermore, we found that downregulation of RhoGDI1 enhances expression of Snail, thereby promoting EMT. Importantly, miR-483-5p levels are positively correlated with β-catenin expression, but are negatively correlated with the levels of RhoGDI1 and ALCAM in human lung adenocarcinoma. Our findings reveal that miR-483-5p is a critical β-catenin–activated prometastatic miRNA and a negative regulator of the metastasis suppressors RhoGDI1 and ALCAM. Cancer Res; 74(11); 3031–42. ©2014 AACR.
Data from Caveolin-1–LRP6 Signaling Module Stimulates Aerobic Glycolysis in Prostate Cancer
Authors: Tahir Salahaldin A. , Yang Guang , Goltsov Alexei , Song Ki-Duk , Ren Chengzhen , Wang Jianxiang , Chang Wenjun , Thompson Timothy C.
Published: March 2024

Abstract
Caveolin 1 (Cav-1) is a plasma membrane–associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein receptor–related protein 6 (LRP6) were reported to be important for the regulation of Wnt-β-catenin (β-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt–β-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results show that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt–mTORC1 signaling and aerobic glycolysis in prostate cancer. Cancer Res; 73(6); 1900–11. ©2012 AACR.
Data from Inhibition of Protein Kinase CK2 Reduces Cyp24a1 Expression and Enhances 1,25-Dihydroxyvitamin D3 Antitumor Activity in Human Prostate Cancer Cells
Authors: Luo Wei , Yu Wei-Dong , Ma Yingyu , Chernov Mikhail , Trump Donald L. , Johnson Candace S.
Published: March 2024

Abstract
Vitamin D has broad range of physiological functions and antitumor effects. 24-Hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 antitumor activity. To isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz-treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3-induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3-mediated target gene expression. Finally, inhibition of CK2 by TBBz or CK2 siRNA significantly enhances 1,25D3-mediated antiproliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3-mediated antitumor effect. Cancer Res; 73(7); 2289–97. ©2013 AACR.
Data from A Meta-analysis of Lung Cancer Gene Expression Identifies PTK7 as a Survival Gene in Lung Adenocarcinoma
Authors: Chen Ron , Khatri Purvesh , Mazur Pawel K. , Polin Melanie , Zheng Yanyan , Vaka Dedeepya , Hoang Chuong D. , Shrager Joseph , Xu Yue , Vicent Silvestre , Butte Atul J. , Sweet-Cordero E. Alejandro
Published: March 2024

Abstract
Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma, we conducted a large-scale meta-analysis of genes specifically overexpressed in adenocarcinoma. We identified an 11-gene signature that was overexpressed consistently in adenocarcinoma specimens relative to normal lung tissue. Six genes in this signature were specifically overexpressed in adenocarcinoma relative to other subtypes of non–small cell lung cancer (NSCLC). Among these genes was the little studied protein tyrosine kinase PTK7. Immunohistochemical analysis confirmed that PTK7 is highly expressed in primary adenocarcinoma patient samples. RNA interference–mediated attenuation of PTK7 decreased cell viability and increased apoptosis in a subset of adenocarcinoma cell lines. Further, loss of PTK7 activated the MKK7–JNK stress response pathway and impaired tumor growth in xenotransplantation assays. Our work defines PTK7 as a highly and specifically expressed gene in adenocarcinoma and a potential therapeutic target in this subset of NSCLC. Cancer Res; 74(10); 2892–902. ©2014 AACR.
Data from Prodigiosin Rescues Deficient p53 Signaling and Antitumor Effects via Upregulating p73 and Disrupting Its Interaction with Mutant p53
Authors: Hong Bo , Prabhu Varun V. , Zhang Shengliang , van den Heuvel A. Pieter J. , Dicker David T. , Kopelovich Levy , El-Deiry Wafik S.
Published: March 2024

Abstract
p53 reactivation offers a broad-based strategy for cancer therapy. In this study, we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53-deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell-cycle arrest and apoptosis in p53-deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot TP53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting antitumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by upregulating p73 and targeting mutant p53/p73 interaction there. Cancer Res; 74(4); 1153–65. ©2013 AACR.
Data from Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma
Authors: Liao Rachel G. , Jung Joonil , Tchaicha Jeremy , Wilkerson Matthew D. , Sivachenko Andrey , Beauchamp Ellen M. , Liu Qingsong , Pugh Trevor J. , Pedamallu Chandra Sekhar , Hayes D. Neil , Gray Nathanael S. , Getz Gad , Wong Kwok-Kin , Haddad Robert I. , Meyerson Matthew , Hammerman Peter S.
Published: March 2024

Abstract
A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC. Cancer Res; 73(16); 5195–205. ©2013 AACR.
Data from Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin
Authors: Zhao Xiao , Gao Song , Ren He , Sun Wei , Zhang Huan , Sun Jianwei , Yang Shengyu , Hao Jihui
Published: March 2024

Abstract
Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal—regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1α expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1α and fascin in PDAC specimens, suggesting that hypoxia and HIF-1α were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1α knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression. Cancer Res; 74(9); 2455–64. ©2014 AACR.
Data from Extracellular Vesicles Modulate the Glioblastoma Microenvironment via a Tumor Suppression Signaling Network Directed by miR-1
Authors: Bronisz Agnieszka , Wang Yan , Nowicki Michal O. , Peruzzi Pierpaolo , Ansari Khairul I. , Ogawa Daisuke , Balaj Leonora , De Rienzo Gianluca , Mineo Marco , Nakano Ichiro , Ostrowski Michael C. , Hochberg Fred , Weissleder Ralph , Lawler Sean E. , Chiocca E. Antonio , Godlewski Jakub
Published: March 2024

Abstract
Extracellular vesicles have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma that identifies miR-1 as an orchestrator of extracellular vesicle function and glioblastoma growth and invasion. Ectopic expression of miR-1 in glioblastoma cells blocked in vivo growth, neovascularization, and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by extracellular vesicles released by cancer stem–like glioblastoma cells. An extracellular vesicle–dependent phenotype defined by glioblastoma invasion, neurosphere growth, and endothelial tube formation was mitigated by loading miR-1 into glioblastoma-derived extracellular vesicles. Protein cargo in extracellular vesicles was characterized to learn how miR-1 directed extracellular vesicle function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in glioblastoma-derived extracellular vesicles, was found to be a direct target of miR-1 control. In addition, extracellular vesicle–derived miR-1 along with other ANXA2 extracellular vesicle networking partners targeted multiple pro-oncogenic signals in cells within the glioblastoma microenvironment. Together, our results showed how extracellular vesicle signaling promotes the malignant character of glioblastoma and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for glioblastoma management. Cancer Res; 74(3); 738–50. ©2013 AACR.
Data from AR-Regulated TWEAK-FN14 Pathway Promotes Prostate Cancer Bone Metastasis
Authors: Yin JuanJuan , Liu Yen-Nien , Tillman Heather , Barrett Ben , Hewitt Stephen , Ylaya Kris , Fang Lei , Lake Ross , Corey Eva , Morrissey Colm , Vessella Robert , Kelly Kathleen
Published: March 2024

Abstract
The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers. Cancer Res; 74(16); 4306–17. ©2014 AACR.
Data from CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist
Authors: Sarvi Sana , Mackinnon Alison C. , Avlonitis Nicolaos , Bradley Mark , Rintoul Robert C. , Rassl Doris M. , Wang Wei , Forbes Stuart J. , Gregory Christopher D. , Sethi Tariq
Published: March 2024

Abstract
Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133+ SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133+ cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting. Cancer Res; 74(5); 1554–65. ©2014 AACR.
Data from CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy
Authors: Ma Yuting , Mattarollo Stephen R. , Adjemian Sandy , Yang Heng , Aymeric Laetitia , Hannani Dalil , Portela Catani João Paulo , Duret Helene , Teng Michele W.L. , Kepp Oliver , Wang Yidan , Sistigu Antonella , Schultze Joachim L. , Stoll Gautier , Galluzzi Lorenzo , Zitvogel Laurence , Smyth Mark J. , Kroemer Guido
Published: March 2024

Abstract
The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell– and T-lymphocyte–dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b+CD11c+Ly6ChighLy6G−MHCII+ dendritic cell–like antigen-presenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen–specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2−/− mice failed to accumulate dendritic cell–like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436–45. ©2013 AACR.
Data from Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells
Authors: Oberg Hans-Heinrich , Peipp Matthias , Kellner Christian , Sebens Susanne , Krause Sarah , Petrick Domantas , Adam-Klages Sabine , Röcken Christoph , Becker Thomas , Vogel Ilka , Weisner Dietrich , Freitag-Wolf Sandra , Gramatzki Martin , Kabelitz Dieter , Wesch Daniela
Published: March 2024

Abstract
The ability of human γδ T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of γδ T-cell–stimulating antigens. In this study, we demonstrate that γδ T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of γδ T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of γδ T cells with the Her2/Vγ9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit γδ T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous γδ T cells for immunotherapy. Cancer Res; 74(5); 1349–60. ©2014 AACR.
Data from HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2
Authors: Cheng Guangcun , Sun Xueqing , Wang Jinglong , Xiao Gang , Wang Xiumin , Fan Xuemei , Zu Lidong , Hao Mingang , Qu Qing , Mao Yan , Xue Yunjing , Wang Jianhua
Published: March 2024

Abstract
The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here, we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC), which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared with other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion, and metastasis, whereas RNAi-mediated silencing of HIC1 in untransformed human breast cells increased their invasive capabilities. Mechanistic investigations identified the small-secreted protein lipocalin-2 (LCN2), as a critical downstream target of HIC1 in TNBC cells. Elevating LCN2 expression in cells expressing HIC1 partially rescued its suppression of cell invasion and metastasis. Notably, autocrine secretion of LCN2 induced by loss of HIC1 activated the AKT pathway through the neutrophil gelatinase–associated lipocalin receptor, which is associated with TNBC progression. Taken together, our findings revealed that the HIC1–LCN2 axis may serve as a subtype-specific prognostic biomarker, providing an appealing candidate target for TNBC therapy. Cancer Res; 74(3); 862–72. ©2013 AACR.
Data from hSETD1A Regulates Wnt Target Genes and Controls Tumor Growth of Colorectal Cancer Cells
Authors: Salz Tal , Li Guangyao , Kaye Frederic , Zhou Lei , Qiu Yi , Huang Suming
Published: March 2024

Abstract
hSETD1A is a member of the trithorax (TrxG) family of histone methyltransferases (HMT) that methylate H3K4 at promoters of active genes. Although misregulation of mixed lineage leukemia (MLL) family proteins has been associated with acute leukemia, the role of hSETD1A in cancer remains unknown. In this study, we report that hSETD1A and its associated H3K4me3 are upregulated in human colorectal cancer cells and patient samples. Depletion of hSETD1A inhibits colorectal cancer cell growth, colony formation, and tumor engraftment. Genome-wide expression profiling of colorectal cancer cells reveals that approximately 50% of Wnt/β-catenin target genes are affected by the hSETD1A knockdown. We further demonstrate that hSETD1A is recruited to promoters of those Wnt signaling target genes through its interaction with β-catenin, a master regulator of the Wnt signaling pathway. The recruitment of the hSETD1A HMT complex confers promoter-associated H3K4me3 that leads to assembly of transcription preinitiation complex and transcriptional activation. Furthermore, the expression levels of hSETD1A are positively correlated with H3K4me3 enrichment at the promoters of Wnt/β-catenin target genes and the aberrant activation of these genes in human colorectal cancer. These results provide new biologic and mechanistic insights into the cooperative role of hSETD1A and β-catenin in regulation of Wnt target genes as well as in colorectal cancer cell growth in vitro and in vivo. Cancer Res; 74(3); 775–86. ©2013 AACR.