bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance
Authors: AlHossiny Midrar , Luo Linlin , Frazier William R. , Steiner Noriko , Gusev Yuriy , Kallakury Bhaskar , Glasgow Eric , Creswell Karen , Madhavan Subha , Kumar Rakesh , Upadhyay Geeta
Published: March 2024

Abstract
Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologs Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E was required for TGFβ signaling and proliferation in breast cancer cells, where they contributed to phosphorylation of Smad1/5 and Smad2/3. Furthermore, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Finally, we found that Ly6K/E promoted drug resistance and facilitated immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGFβ in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention. Cancer Res; 76(11); 3376–86. ©2016 AACR.
Data from A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors
Authors: Zhong Haihong , Davis April , Ouzounova Maria , Carrasco Rosa A. , Chen Cui , Breen Shannon , Chang Yong S. , Huang Jiaqi , Liu Zheng , Yao Yihong , Hurt Elaine , Moisan Jacques , Fung Michael , Tice David A. , Clouthier Shawn G. , Xiao Zhan , Wicha Max S. , Korkaya Hasan , Hollingsworth Robert E.
Published: March 2024

Abstract
Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells by targeting the CD44+CD24− cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance. Cancer Res; 76(2); 480–90. ©2016 AACR.
Data from Candidate Antimetastasis Drugs Suppress the Metastatic Capacity of Breast Cancer Cells by Reducing Membrane Fluidity
Authors: Zhao Weina , Prijic Sara , Urban Bettina C. , Tisza Michael J. , Zuo Yan , Li Lin , Tan Zhi , Chen Xiaoling , Mani Sendurai A. , Chang Jeffrey T.
Published: March 2024

Abstract
Despite the high mortality from metastatic cancer, therapeutic targets to prevent metastasis are limited. Efforts to identify genetic aberrations that predispose tumors to metastasis have been mostly unsuccessful. To understand the nature of candidate targets for metastatic disease, we performed an in silico screen to identify drugs that can inhibit a gene expression signature associated with epithelial–mesenchymal transition (EMT). Compounds discovered through this method, including those previously identified, appeared to restrict metastatic capacity through a common mechanism, the ability to modulate the fluidity of cell membranes. Treatment of breast cancer cell lines with the putative antimetastasis agents reduced membrane fluidity, resulting in decreased cell motility, stem cell–like properties, and EMT in vitro, and the drugs also inhibited spontaneous metastasis in vivo. When fluidity was unchanged, the antimetastasis compounds could no longer restrict metastasis, indicating a causal association between fluidity and metastasis. We further demonstrate that fluidity can be regulated by cellular cholesterol flux, as the cholesterol efflux channel ABCA1 potentiated metastatic behaviors in vitro and in vivo. The requirement for fluidity was further supported by the finding in breast cancer patients that ABCA1 was overexpressed in 41% of metastatic tumors, reducing time to metastasis by 9 years. Collectively, our findings reveal increased membrane fluidity as a necessary cellular feature of metastatic potential that can be controlled by many currently available drugs, offering a viable therapeutic opportunity to prevent cancer metastasis. Cancer Res; 76(7); 2037–49. ©2016 AACR.
Data from Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression
Authors: Picon-Ruiz Manuel , Pan Chendong , Drews-Elger Katherine , Jang Kibeom , Besser Alexandra H. , Zhao Dekuang , Morata-Tarifa Cynthia , Kim Minsoon , Ince Tan A. , Azzam Diana J. , Wander Seth A. , Wang Bin , Ergonul Burcu , Datar Ram H. , Cote Richard J. , Howard Guy A. , El-Ashry Dorraya , Torné-Poyatos Pablo , Marchal Juan A. , Slingerland Joyce M.
Published: March 2024

Abstract
Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell–like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491–504. ©2016 AACR.
Data from Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling
Authors: Quan Ming , Cui Jiujie , Xia Tian , Jia Zhiliang , Xie Dacheng , Wei Daoyan , Huang Suyun , Huang Qian , Zheng Shaojiang , Xie Keping
Published: March 2024

Abstract
Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer. Cancer Res; 75(22); 4778–89. ©2015 AACR.
Data from An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers
Authors: Prueitt Robyn L. , Wallace Tiffany A. , Glynn Sharon A. , Yi Ming , Tang Wei , Luo Jun , Dorsey Tiffany H. , Stagliano Katherine E. , Gillespie John W. , Hudson Robert S. , Terunuma Atsushi , Shoe Jennifer L. , Haines Diana C. , Yfantis Harris G. , Han Misop , Martin Damali N. , Jordan Symone V. , Borin James F. , Naslund Michael J. , Alexander Richard B. , Stephens Robert M. , Loffredo Christopher A. , Lee Dong H. , Putluri Nagireddy , Sreekumar Arun , Hurwitz Arthur A. , Ambs Stefan
Published: March 2024

Abstract
Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer–prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055–65. ©2015 AACR.
Data from Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer
Authors: Jain Shalini , Wang Xiao , Chang Chia-Chi , Ibarra-Drendall Catherine , Wang Hai , Zhang Qingling , Brady Samuel W. , Li Ping , Zhao Hong , Dobbs Jessica , Kyrish Matt , Tkaczyk Tomasz S. , Ambrose Adrian , Sistrunk Christopher , Arun Banu K. , Richards-Kortum Rebecca , Jia Wei , Seewaldt Victoria L. , Yu Dihua
Published: March 2024

Abstract
Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER+) breast cancer development, but estrogen receptor–negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER− mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers. Cancer Res; 75(22); 4863–75. ©2015 AACR.
Data from Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens
Authors: Uttam Shikhar , Pham Hoa V. , LaFace Justin , Leibowitz Brian , Yu Jian , Brand Randall E. , Hartman Douglas J. , Liu Yang
Published: March 2024

Abstract
Early cancer detection currently relies on screening the entire at-risk population, as with colonoscopy and mammography. Therefore, frequent, invasive surveillance of patients at risk for developing cancer carries financial, physical, and emotional burdens because clinicians lack tools to accurately predict which patients will actually progress into malignancy. Here, we present a new method to predict cancer progression risk via nanoscale nuclear architecture mapping (nanoNAM) of unstained tissue sections based on the intrinsic density alteration of nuclear structure rather than the amount of stain uptake. We demonstrate that nanoNAM detects a gradual increase in the density alteration of nuclear architecture during malignant transformation in animal models of colon carcinogenesis and in human patients with ulcerative colitis, even in tissue that appears histologically normal according to pathologists. We evaluated the ability of nanoNAM to predict “future” cancer progression in patients with ulcerative colitis who did and did not develop colon cancer up to 13 years after their initial colonoscopy. NanoNAM of the initial biopsies correctly classified 12 of 15 patients who eventually developed colon cancer and 15 of 18 who did not, with an overall accuracy of 85%. Taken together, our findings demonstrate great potential for nanoNAM in predicting cancer progression risk and suggest that further validation in a multicenter study with larger cohorts may eventually advance this method to become a routine clinical test. Cancer Res; 75(22); 4718–27. ©2015 AACR.
Data from Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells
Authors: Cao Ji , Wang Yijie , Dong Rong , Lin Guanyu , Zhang Ning , Wang Jing , Lin Nengming , Gu Yongchuan , Ding Ling , Ying Meidan , He Qiaojun , Yang Bo
Published: March 2024

Abstract
Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. Cancer Res; 75(22); 4839–51. ©2015 AACR.
Data from Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer
Authors: Rao Chinthalapally V. , Janakiram Naveena B. , Madka Venkateshwar , Kumar Gaurav , Scott Edgar J. , Pathuri Gopal , Bryant Taylor , Kutche Hannah , Zhang Yuting , Biddick Laura , Gali Hariprasad , Zhao Yan D. , Lightfoot Stan , Mohammed Altaf
Published: March 2024

Abstract
Pancreatic cancer is an aggressive neoplasm with almost uniform lethality and a 5-year survival rate of 7%. Several overexpressed mucins that impede drug delivery to pancreatic tumors have been therapeutically targeted, but enzymes involved in mucin biosynthesis have yet to be preclinically evaluated as potential targets. We used survival data from human patients with pancreatic cancer, next-generation sequencing of genetically engineered Kras-driven mouse pancreatic tumors and human pancreatic cancer cells to identify the novel core mucin-synthesizing enzyme GCNT3 (core 2 β-1,6 N-acetylglucosaminyltransferase). In mouse pancreatic cancer tumors, GCNT3 upregulation (103-fold; P < 0.0001) was correlated with increased expression of mucins (5 to 87-fold; P < 0.04–0.0003). Aberrant GCNT3 expression was also associated with increased mucin production, aggressive tumorigenesis, and reduced patient survival, and CRISPR-mediated knockout of GCNT3 in pancreatic cancer cells reduced proliferation and spheroid formation. Using in silico small molecular docking simulation approaches, we identified talniflumate as a novel inhibitor that selectively binds to GCNT3. In particular, docking predictions suggested that three notable hydrogen bonds between talniflumate and GCNT3 contribute to a docking affinity of −8.3 kcal/mol. Furthermore, talniflumate alone and in combination with low-dose gefitinib reduced GCNT3 expression, leading to the disrupted production of mucins in vivo and in vitro. Collectively, our findings suggest that targeting mucin biosynthesis through GCNT3 may improve drug responsiveness, warranting further development and investigation in preclinical models of pancreatic tumorigenesis. Cancer Res; 76(7); 1965–74. ©2016 AACR.
Data from Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway
Authors: Jakubek Yasminka , Lang Wenhua , Vattathil Selina , Garcia Melinda , Xu Li , Huang Lili , Yoo Suk-Young , Shen Li , Lu Wei , Chow Chi-Wan , Weber Zachary , Davies Gareth , Huang Jing , Behrens Carmen , Kalhor Neda , Moran Cesar , Fujimoto Junya , Mehran Reza , El-Zein Randa , Swisher Stephen G. , Wang Jing , Fowler Jerry , Spira Avrum E. , Ehli Erik A. , Wistuba Ignacio I. , Scheet Paul , Kadara Humam
Published: March 2024

Abstract
Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non–small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. Cancer Res; 76(13); 3676–83. ©2016 AACR.
Data from Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis
Authors: Na Youjin , Kaul Sunil C. , Ryu Jihoon , Lee Jung-Sun , Ahn Hyo Min , Kaul Zeenia , Kalra Rajkumar S. , Li Ling , Widodo Nashi , Yun Chae-Ok , Wadhwa Renu
Published: March 2024

Abstract
Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K–Akt, and JAK–STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), β-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNA-mediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9); 2754–65. ©2016 AACR.
Data from Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen
Authors: Ning Chengcheng , Xie Bingying , Zhang Lin , Li Chunsheng , Shan Weiwei , Yang Bingyi , Luo Xuezhen , Gu Chao , He Qizhi , Jin Hongyan , Chen Xiaojun , Zhang Zhenbo , Feng Youji
Published: March 2024

Abstract
Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68+CD163+ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68+CD163+ macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. Cancer Res; 76(6); 1354–66. ©2016 AACR.
Data from RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3
Authors: Xie Min , Vesuna Farhad , Tantravedi Saritha , Bol Guus M. , Heerma van Voss Marise R. , Nugent Katriana , Malek Reem , Gabrielson Kathleen , van Diest Paul J. , Tran Phuoc T. , Raman Venu
Published: March 2024

Abstract
Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second highest cause of cancer-related mortality. We identified an RNA helicase gene, DDX3 (DDX3X), which is overexpressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in the aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3. Functional studies indicated that RK-33 preferentially bound to DDX3 and perturbed its activity. RK-33 treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) decreased proliferation and induced a G1 phase cell-cycle arrest. Conversely, the low DDX3–expressing cell line, PC3, exhibited few changes following RK-33 treatment. Importantly, combination studies using RK-33 and radiation exhibited synergistic effects both in vitro and in a xenograft model of prostate cancer demonstrating the role of RK-33 as a radiosensitizer. Taken together, these results indicate that blocking DDX3 by RK-33 in combination with radiation treatment is a viable option for treating locally advanced prostate cancer. Cancer Res; 76(21); 6340–50. ©2016 AACR.
Data from UGT2B17 Expedites Progression of Castration-Resistant Prostate Cancers by Promoting Ligand-Independent AR Signaling
Authors: Li Haolong , Xie Ning , Chen Ruiqi , Verreault Mélanie , Fazli Ladan , Gleave Martin E. , Barbier Olivier , Dong Xuesen
Published: March 2024

Abstract
Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701–11. ©2016 AACR.
Data from NOTCH1 Signaling Regulates Self-Renewal and Platinum Chemoresistance of Cancer Stem–like Cells in Human Non–Small Cell Lung Cancer
Authors: Zhang Yun , Xu Wei , Guo Huiqin , Zhang Yanmei , He Yuexi , Lee Sau Har , Song Xin , Li Xiaoyan , Guo Yongqing , Zhao Yunlong , Ding Cheng , Ning Fei , Ma Yuanyuan , Lei Qun-Ying , Hu Xiaoyu , Li Shengnan , Guo Wei
Published: March 2024

Abstract
Cancer stem–like cells (CSC) are thought to drive tumor initiation, metastasis, relapse, and therapeutic resistance, but their specific pathogenic characters in many cancers, including non–small cell lung cancer (NSCLC), have yet to be well defined. Here, we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166+CD49fhiCD104−Lin− LCSC present in all human specimens of NSCLC examined, regardless of their histologic subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a γ-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo. Overall, our results define the pathogenic characters of a cancer stem–like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease. Cancer Res; 77(11); 3082–91. ©2017 AACR.
Data from Immune-Stimulatory Effects of Rapamycin Are Mediated by Stimulation of Antitumor γδ T Cells
Authors: Dao Vinh , Liu Yang , Pandeswara Srilakshmi , Svatek Robert S. , Gelfond Jonathan A. , Liu Aijie , Hurez Vincent , Curiel Tyler J.
Published: March 2024

Abstract
The FDA-approved mTOR inhibitor rapamycin mediates important immune effects, but its contributions to the anticancer effects of the drug are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation of γδ T cells. In a well-established mouse model of carcinogen and inflammation-driven skin carcinogenesis, IFNγ recruited γδ TCRmid T cells to the epidermis where rapamycin boosted their perforin-dependent antitumor properties. These antitumor cells were mostly Vγ5−Vγ4−Vγ1− in phenotype. IFNγ signals were required in both hematopoietic and nonhematopoietic cells for rapamycin to optimally promote epidermal infiltration of γδ TCRmid T cells, as mediated by CXCR3–CXCL10 interactions, along with the antitumor effects of these cells. In mouse xenograft models of human squamous cell carcinoma, rapamycin improved human γδ T-cell–mediated cancer cell killing. Our results identify immune mechanisms for the cancer prevention and treatment properties of rapamycin, challenging the paradigm that mTOR inhibition acts primarily by direct action on tumor cells. Cancer Res; 76(20); 5970–82. ©2016 AACR.
Data from SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2
Authors: Eytan Danielle F. , Snow Grace E. , Carlson Sophie , Derakhshan Adeeb , Saleh Anthony , Schiltz Stephen , Cheng Hui , Mohan Suresh , Cornelius Shaleeka , Coupar Jamie , Sowers Anastasia L. , Hernandez Lidia , Mitchell James B. , Annunziata Christina M. , Chen Zhong , Van Waes Carter
Published: March 2024

Abstract
Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFα or TRAIL and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines and birinapant alone also induced significant G2–M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFα, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNFα, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/− BIRC2. These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. Cancer Res; 76(18); 5442–54. ©2016 AACR.
Data from Monitoring Tumor Response to Antivascular Therapy Using Non-Contrast Intravoxel Incoherent Motion Diffusion-Weighted MRI
Authors: Shi Changzheng , Liu Dexiang , Xiao Zeyu , Zhang Dong , Liu Guanfu , Liu Guanshu , Chen Hanwei , Luo Liangping
Published: March 2024

Abstract
Antivascular therapy is a promising approach to the treatment of non–small cell lung cancer (NSCLC), where an imaging modality capable of longitudinally monitoring treatment response could provide early prediction of the outcome. In this study, we sought to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion MRI to quantitatively assess the efficacy of the treatments of a vascular-disrupting agent CA4P or its combination with bevacizumab on experimental NSCLC tumors. CA4P caused a strong but reversible effect on tumor vasculature; all perfusion-related parameters—D*, f, fD*, and Ktrans—initially showed a decrease of 30% to 60% at 2 hours and then fully recovered to baseline on day 2 for CA4P treatment or on days 4 to 8 for CA4P + bevacizumab treatment; the diffusion coefficient in tumors decreased initially at 2 hours and then increased from day 2 to day 8. We observed a good correlation between IVIM parameters and dynamic contrast-enhanced MRI (DCE-MRI; Ktrans). We also found that the relative change in f and fD* at 2 hours correlated well with changes in tumor volume on day 8. In conclusion, our results suggest that IVIM is a promising alternative to DCE-MRI for the assessment of the change in tumor perfusion as a result of antivascular agents and can be used to predict the efficacy of antivascular therapies without the need for contrast media injection. Cancer Res; 77(13); 3491–501. ©2017 AACR.
Data from CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
Authors: Wang Xin , Li Liping , Wu Yuanzhong , Zhang Ruhua , Zhang Meifang , Liao Dan , Wang Gang , Qin Ge , Xu Rui-hua , Kang Tiebang
Published: March 2024

Abstract
Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.
Data from αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor
Authors: Lu Huimin , Wang Tao , Li Jing , Fedele Carmine , Liu Qin , Zhang Jianzhong , Jiang Zhong , Jain Dhanpat , Iozzo Renato V. , Violette Shelia M. , Weinreb Paul H. , Davis Roger J. , Gioeli Daniel , FitzGerald Thomas J. , Altieri Dario C. , Languino Lucia R.
Published: March 2024

Abstract
Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Ptenpc−/−, carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, because it is not regulated by a different αv-containing integrin, αvβ3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of αvβ6-expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor–increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy. Cancer Res; 76(17); 5163–74. ©2016 AACR.
Data from Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer
Authors: Wen Di , Peng Yang , Lin Feng , Singh Rakesh K. , Mahato Ram I.
Published: March 2024

Abstract
Treatment of prostate cancer with paclitaxel often fails due to the development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that codelivery of paclitaxel and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes paclitaxel-resistant prostate cancer cells, killing both cancer stem–like cells (CSC) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. Paclitaxel and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol; PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70% ± 0.10% and 5.34% ± 0.02% for paclitaxel and rubone, respectively, controlling a drug release of 60.20% ± 2.67% and 60.62% ± 4.35% release of paclitaxel and rubone at 24 hours. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing paclitaxel concentration. Coincubation with a miR-34a inhibitor diminished the effect of rubone. Paclitaxel IC50 in PC3 and PC3-TXR cells was 55.6 and 2,580 nmol/L, respectively, but decreased to 49.8 and 93.2 nmol/L when treated in combination with rubone, demonstrating a reversal of paclitaxel resistance by rubone. Systemic administration of micelles carrying paclitaxel and rubone inhibited orthotopic prostate tumor growth in nude mice, compared with monotherapy, by reversing the expression of miR-34a, SIRT1, cyclin D1, and E-cadherin. In summary, our results showed how rubone acts as an efficient small-molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of paclitaxel in paclitaxel-resistant prostate cancer. Cancer Res; 77(12); 3244–54. ©2017 AACR.
Data from IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment
Authors: Fang Min , Li Yongkui , Huang Kai , Qi Shanshan , Zhang Jian , Zgodzinski Witold , Majewski Marek , Wallner Grzegorz , Gozdz Stanislaw , Macek Pawel , Kowalik Artur , Pasiarski Marcin , Grywalska Ewelina , Vatan Linda , Nagarsheth Nisha , Li Wei , Zhao Lili , Kryczek Ilona , Wang Guobin , Wang Zheng , Zou Weiping , Wang Lin
Published: March 2024

Abstract
The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735–45. ©2017 AACR.
Data from Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency
Authors: Zhao Fang , Sucker Antje , Horn Susanne , Heeke Christina , Bielefeld Nicola , Schrörs Barbara , Bicker Anne , Lindemann Monika , Roesch Alexander , Gaudernack Gustav , Stiller Mathias , Becker Jürgen C. , Lennerz Volker , Wölfel Thomas , Schadendorf Dirk , Griewank Klaus , Paschen Annette
Published: March 2024

Abstract
Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8+ T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Junhigh/MITFlow phenotype, possibly associated with immunosuppression, which contrasted with a c-Junlow/MITFhigh phenotype of T cell–edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347–58. ©2016 AACR.
Data from Targeting FBW7 as a Strategy to Overcome Resistance to Targeted Therapy in Non–Small Cell Lung Cancer
Authors: Ye Mingxiang , Zhang Yong , Zhang Xinxin , Zhang Jianbin , Jing Pengyu , Cao Liang , Li Nan , Li Xia , Yao Libo , Zhang Jian
Published: March 2024

Abstract
Inhibition of EGFR and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non–small cell lung cancer (NSCLC) patients with distinct clinicopathologic features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/ERK–independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of antiapoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. ERK cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor–resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/ERK–independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy. Cancer Res; 77(13); 3527–39. ©2017 AACR.
Data from Improving the Performance of Somatic Mutation Identification by Recovering Circulating Tumor DNA Mutations
Authors: Fu Yu , Jovelet Cécile , Filleron Thomas , Pedrero Marion , Motté Nelly , Boursin Yannick , Luo Yufei , Massard Christophe , Campone Mario , Levy Christelle , Diéras Véronique , Bachelot Thomas , Garrabey Julie , Soria Jean-Charles , Lacroix Ludovic , André Fabrice , Lefebvre Celine
Published: March 2024

Abstract
DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53. We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell–free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954–61. ©2016 AACR.