bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Endothelin Promotes Colorectal Tumorigenesis by Activating YAP/TAZ
Authors: Wang Zhen , Liu Peng , Zhou Xin , Wang Tianxiang , Feng Xu , Sun Yi-Ping , Xiong Yue , Yuan Hai-Xin , Guan Kun-Liang
Published: March 2023

Abstract
Endothelin receptor A (ETAR) promotes tumorigenesis by stimulating cell proliferation, migration, and survival. However, the mechanism of ETAR in promoting tumor growth is largely unknown. In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription coactivators of the Hippo tumor suppressor pathway. Endothelin-1 treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells. ETAR stimulation acted via downstream G-protein Gαq/11 and Rho GTPase to suppress the Hippo pathway, thus leading to YAP/TAZ activation, which was required for ETAR-induced tumorigenesis. Overall, these results indicate a critical role of the YAP/TAZ axis in ETAR signaling. Cancer Res; 77(9); 2413–23. ©2017 AACR.
Data from Scavenger Receptor A1 Prevents Metastasis of Non–Small Cell Lung Cancer via Suppression of Macrophage Serum Amyloid A1
Authors: Zhang Yan , Wei Yongyue , Jiang Bin , Chen Lili , Bai Hui , Zhu Xudong , Li Xiaoyu , Zhang Hanwen , Yang Qing , Ma Junqing , Xu Yong , Ben Jingjing , Christiani David C. , Chen Qi
Published: March 2023

Abstract
Mechanisms of cross-talk between tumor cells and tumor-associated macrophages (TAM), which drive metastasis, are not fully understood. Scavenger receptor A1 (SR-A1) expressed primarily in macrophages has been associated with lung tumorigenesis. In this study, we used population genetics, transcriptomics, and functional analyses to uncover how SR-A1 is involved in lung cancer and its prognosis. SR-A1 genetic variants were investigated for possible association with survival of advanced stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were associated significantly with poor overall survival in this cohort. Data from The Cancer Genome Atlas showed considerable downregulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from mice genetically deficient for SR-A1 exhibited accelerated metastasis in a model of lung cancer. On the other hand, tumor cell seeding, migration, and invasion, as well as macrophage accumulation in lung cancer tissue, were enhanced in SR-A1–deficient mice. SR-A1 deletion upregulated serum amyloid A1 (SAA1) in macrophages via MAPK/IκB/NFκB signaling. SAA1 promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. Overall, our findings show how SR-A1 suppresses lung cancer metastasis by downregulating SAA1 production in TAMs. Cancer Res; 77(7); 1586–98. ©2017 AACR.
Data from Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
Authors: Isobe Tomoya , Seki Masafumi , Yoshida Kenichi , Sekiguchi Masahiro , Shiozawa Yusuke , Shiraishi Yuichi , Kimura Shunsuke , Yoshida Misa , Inoue Yoshikage , Yokoyama Akira , Kakiuchi Nobuyuki , Suzuki Hiromichi , Kataoka Keisuke , Sato Yusuke , Kawai Tomoko , Chiba Kenichi , Tanaka Hiroko , Shimamura Teppei , Kato Motohiro , Iguchi Akihiro , Hama Asahito , Taguchi Tomoaki , Akiyama Masaharu , Fujimura Junya , Inoue Akiko , Ito Tsuyoshi , Deguchi Takao , Kiyotani Chikako , Iehara Tomoko , Hosoi Hajime , Oka Akira , Sanada Masashi , Tanaka Yukichi , Hata Kenichiro , Miyano Satoru , Ogawa Seishi , Takita Junko
Published: March 2023

Abstract
Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.

Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.
Data from WNT/β-Catenin Directs Self-Renewal Symmetric Cell Division of hTERThigh Prostate Cancer Stem Cells
Authors: Zhang Kai , Guo Yanjing , Wang Xue , Zhao Huifang , Ji Zhongzhong , Cheng Chaping , Li Li , Fang Yuxiang , Xu Dawei , Zhu Helen He , Gao Wei-Qiang
Published: March 2023

Abstract
Cancer stem-like cells (CSC) drive cancer progression and recurrence. Self-renewal expansion of CSC is achieved through symmetric cell division, yet how external stimuli affect intracellular regulatory programs of CSC division modes and stemness remains obscure. Here, we report that the hTERThigh prostate cancer cells exhibit CSC properties, including a stem cell–associated gene expression signature, long-term tumor-propagating capacity and epithelial-to-mesenchymal transition. In promoting the self-renewal symmetric division of hTERThigh prostate cancer cells, WNT3a dramatically decreased the ratio of hTERThigh prostate cancer cells undergoing asymmetric division. Increased WNT/β-catenin signal activation was also detected in hTERThigh prostate cancer cells. hTERT-mediated CSC properties were at least partially dependent on β-catenin. These findings provide novel cellular and molecular mechanisms for the self-renewal of CSC orchestrated by tumor microenvironmental stimuli and intracellular signals. Cancer Res; 77(9); 2534–47. ©2017 AACR.
Data from Attenuated TRAF3 Fosters Activation of Alternative NF-κB and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers
Authors: Zhang Jialing , Chen Tony , Yang Xinping , Cheng Hui , Späth Stephan S. , Clavijo Paul E. , Chen Jianhong , Silvin Christopher , Issaeva Natalia , Su Xiulan , Yarbrough Wendell G. , Annunziata Christina M. , Chen Zhong , Van Waes Carter
Published: March 2023

Abstract
Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling the modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF receptor–associated factor 3 (TRAF3). TRAF3 has been implicated as a negative regulator of alternative NF-κB pathway activation and activator of antiviral type I IFN response to other DNA viruses. How TRAF3 alterations affect pathogenesis of HPV+ HNSCC has not been extensively investigated. Here, we report that TRAF3-deficient HPV+ tumors and cell lines exhibit increased expression of alternative NF-κB pathway components and transcription factors NF-κB2/RELB. Overexpression of TRAF3 in HPV+ cell lines with decreased endogenous TRAF3 inhibited NF-κB2/RELB expression, nuclear localization, and NF-κB reporter activity, while increasing the expression of IFNA1 mRNA and protein and sensitizing cells to its growth inhibition. Overexpression of TRAF3 also enhanced TP53 and RB tumor suppressor proteins and decreased HPV E6 oncoprotein in HPV+ cells. Correspondingly, TRAF3 inhibited cell growth, colony formation, migration, and resistance to TNFα and cisplatin-induced cell death. Conversely, TRAF3 knockout enhanced colony formation and proliferation of an HPV+ HNSCC line expressing higher TRAF3 levels. Together, these findings support a functional role of TRAF3 as a tumor suppressor modulating established cancer hallmarks in HPV+ HNSCC.

Significance: These findings report the functional role of TRAF3 as a tumor suppressor that modulates the malignant phenotype of HPV+ head and neck cancers. Cancer Res; 78(16); 4613–26. ©2018 AACR.
Data from Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer
Authors: Saputra Elysia C. , Huang Lu , Chen Yihui , Tucker-Kellogg Lisa
Published: March 2023

Abstract
The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them “proefficacy” strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them “antiresistance” strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy.

Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 2419–31. ©2018 AACR.
Data from SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation
Authors: Yang Xin , Wang Zhe , Li Xin , Liu Boya , Liu Minghui , Liu Lu , Chen Shuaiyi , Ren Mengmeng , Wang Yankun , Yu Miao , Wang Bo , Zou Junhua , Zhu Wei-Guo , Yin Yuxin , Gu Wei , Luo Jianyuan
Published: March 2023

Abstract
The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.

Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372–86. ©2017 AACR.
Data from PTBP3-Mediated Regulation of ZEB1 mRNA Stability Promotes Epithelial–Mesenchymal Transition in Breast Cancer
Authors: Hou Pingfu , Li Lin , Chen Fang , Chen Yansu , Liu Hui , Li Jingjing , Bai Jin , Zheng Junnian
Published: March 2023

Abstract
The RNA polypyrimidine tract-binding protein PTBP3 is a little studied paralog of PTBP1, which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial–mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and to enhance cell migration, invasion, and cancer stem-like cell properties. PTBP3 regulated expression of the EMT regulatory transcription factor ZEB1 by binding the 3′UTR of its mRNA, thereby preventing its degradation. Conversely, ZEB1 ablation blocked the ability of PTBP3 to induce EMT. Overall, our findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3, suggesting its candidacy as a theranostic target.

Significance: These findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3, suggesting its candidacy as a theranostic target. Cancer Res; 78(2); 387–98. ©2017 AACR.
Data from Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis
Authors: Ruprecht Benjamin , Zaal Esther A. , Zecha Jana , Wu Wei , Berkers Celia R. , Kuster Bernhard , Lemeer Simone
Published: March 2023

Abstract
HER2/ERBB2–overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers. Cancer Res; 77(8); 1842–53. ©2017 AACR.
Data from Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells
Authors: Liu Chang , Nie Danian , Li Juan , Du Xin , Lu Yuhong , Li Yangqiu , Zhou Jingfeng , Jin Yanli , Pan Jingxuan
Published: March 2023

Abstract
Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2–M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.

Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522–36. ©2018 AACR.
Data from Cancer-Specific and General Nutritional Scores and Cancer Risk: Results from the Prospective NutriNet-Santé Cohort
Authors: Lavalette Céline , Adjibade Moufidath , Srour Bernard , Sellem Laury , Fiolet Thibault , Hercberg Serge , Latino-Martel Paule , Fassier Philippine , Deschasaux Mélanie , Kesse-Guyot Emmanuelle , Touvier Mathilde
Published: March 2023

Abstract
Several national and international authorities have proposed nutritional and lifestyle recommendations with the aim of improving health of the general population. Scores of adherence to these recommendations can be calculated at the individual level. Here, we investigated the associations between four nutritional scores and overall, breast, prostate, and colorectal cancer risk in a large prospective population-based cohort: the cancer-specific World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) score, the Alternate Healthy Eating Index 2010 (AHEI-2010), a score based on adherence to the Mediterranean diet (MEDI-LITE), and the French National Nutrition Health Program-Guideline Score (PNNS-GS). This study included 41,543 participants aged ≥40 years from the NutriNet-Santé cohort (2009–2017). A total of 1,489 overall incident cancers were diagnosed. A one-point increment of the WCRF/AICR score was significantly associated with decreased overall [12%; 95% confidence interval (CI), 8%–16%; P < 0.0001], breast (14%; 95% CI, 6%–21%; P = 0.001), and prostate (12%; 95% CI, 0%–22%; P = 0.05) cancer risks. Hazard ratio for colorectal cancer risk was 0.86 (95% CI, 0.72–1.03; P = 0.09). The PNNS-GS score was associated with reduced colorectal cancer risk (P = 0.04) and AHEI-2010 was associated with reduced overall cancer risk (P = 0.03). The WCRF/AICR score performed best. Compared with other tested scores, it included a stronger penalty for alcohol, which is a major risk factor for several cancer sites. Better adherence to nutritional recommendations, especially those designed for cancer prevention, could substantially contribute to decreased cancer incidence.

Significance: This large prospective population-based cohort study suggests that following dietary recommendations such as the ones proposed by the World Cancer Research Fund/American Institute for Cancer Research could significantly contribute to cancer prevention. Cancer Res; 78(15); 4427–35. ©2018 AACR.
Data from Solid Tumor–Induced Immune Regulation Alters the GvHD/GvT Paradigm after Allogenic Bone Marrow Transplantation
Authors: Dang Nana , Lin Yuan , Rutgeerts Omer , Sagaert Xavier , Billiau An D. , Waer Mark , Sprangers Ben
Published: March 2023

Abstract
Growth of solid tumors is often associated with the development of an immunosuppressive tumor microenvironment (TME). It has been suggested that the influence of the TME may extend beyond the local tumor and results in systemic immunosuppression. Here, we utilize two murine cancer models to explore the influence of solid tumors on the occurrence of alloreactivity-driven GvHD and graft-versus-solid tumor (GvT) effects following MHC-mismatched allogeneic bone marrow transplantation (allo-BMT). Melanoma- or colon carcinoma–bearing C57BL/6 mice did not develop GvHD after BMT even when the bone marrow inoculum was supplemented with donor-type splenocytes. This protection against GvHD required the presence of tumors because its resection prior to allo-BMT promptly resulted in development of GvHD. In addition, tumor-bearing mice given T-cell–depleted allo-BMT (allo-TCD-BMT) failed to develop GvHD and also showed significantly stronger GvT effects than mice given allo-BMT. The GvT effects in allo-TCD-BMT recipients were associated with profound changes in tumor-infiltrating cells compared with that in allo-BMT recipients, with significantly reduced donor-derived regulatory T cells (Treg), increased cytotoxic effector (IFNγhi) CD8 T cells, and increased M1 macrophages (iNOShi, arginaselo, and IL10lo); the use of macrophage-depleted bone marrow abrogated the GvT effects. Collectively, these results indicate that the presence of M1 macrophages may disrupt the generation of donor-type Treg cells so that the immunomodulatory effect of the TME can affect systemic immunity.
Significance:
These findings show that cells such as T cells or macrophages in the bone marrow inoculum may interfere with the systemic and local immune reactivity against tumors.
Data from MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway
Authors: Yu Tao , Zhao Yingjun , Hu Zhixiang , Li Jing , Chu Dandan , Zhang Jiwei , Li Zhe , Chen Bing , Zhang Xiao , Pan Hongyu , Li Shengli , Lin Hechun , Liu Lei , Yan Mingxia , He Xianghuo , Yao Ming
Published: March 2023

Abstract
Long noncoding RNAs (lncRNA) participate in carcinogenesis and tumor progression in lung cancer. Here, we report the identification of a lncRNA signature associated with metastasis of non–small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a coactivator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC. Cancer Res; 77(21); 5782–94. ©2017 AACR.
Data from dcmqi: An Open Source Library for Standardized Communication of Quantitative Image Analysis Results Using DICOM
Authors: Herz Christian , Fillion-Robin Jean-Christophe , Onken Michael , Riesmeier Jörg , Lasso Andras , Pinter Csaba , Fichtinger Gabor , Pieper Steve , Clunie David , Kikinis Ron , Fedorov Andriy
Published: March 2023

Abstract
Quantitative analysis of clinical image data is an active area of research that holds promise for precision medicine, early assessment of treatment response, and objective characterization of the disease. Interoperability, data sharing, and the ability to mine the resulting data are of increasing importance, given the explosive growth in the number of quantitative analysis methods being proposed. The Digital Imaging and Communications in Medicine (DICOM) standard is widely adopted for image and metadata in radiology. dcmqi (DICOM for Quantitative Imaging) is a free, open source library that implements conversion of the data stored in commonly used research formats into the standard DICOM representation. dcmqi source code is distributed under BSD-style license. It is freely available as a precompiled binary package for every major operating system, as a Docker image, and as an extension to 3D Slicer. Installation and usage instructions are provided in the GitHub repository at https://github.com/qiicr/dcmqi. Cancer Res; 77(21); e87–90. ©2017 AACR.
Data from FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB–BMP Signaling Cross-talk
Authors: Lau Marco Chi-Chung , Ng Kai Yu , Wong Tin Lok , Tong Man , Lee Terence K. , Ming Xiao-Yan , Law Simon , Lee Nikki P. , Cheung Annie L. , Qin Yan-Ru , Chan Kwok Wah , Ning Wen , Guan Xin-Yuan , Ma Stephanie
Published: March 2023

Abstract
Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, and molecular markers to improve early detection and predict outcomes are greatly needed. Here, we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs, where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q, where it is located, occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal, and cisplatin resistance in vitro and tumorigenicity and distant metastasis in vivo. Conversely, FSTL1 attenuation by shRNA or neutralizing antibody elicited the opposite effects in ESCC cells. mRNA profiling analyses suggested that FSTL1 drives ESCC oncogenesis and metastasis through various pathways, with deregulation of NFκB and BMP signaling figuring prominently. Cross-talk between the NFκB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NFκB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinating NFκB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in this disease setting. Cancer Res; 77(21); 5886–99. ©2017 AACR.
Data from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
Authors: Brand Toni M. , Hartmann Stefan , Bhola Neil E. , Li Hua , Zeng Yan , O'Keefe Rachel A. , Ranall Max V. , Bandyopadhyay Sourav , Soucheray Margaret , Krogan Nevan J. , Kemp Carolyn , Duvvuri Umamaheswar , LaVallee Theresa , Johnson Daniel E. , Ozbun Michelle A. , Bauman Julie E. , Grandis Jennifer R.
Published: March 2023

Abstract
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.

Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383–95. ©2018 AACR.
Data from Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer
Authors: Wang Zebin , Grosskurth Shaun E. , Cheung Tony , Petteruti Philip , Zhang Jingwen , Wang Xin , Wang Wenxian , Gharahdaghi Farzin , Wu Jiaquan , Su Nancy , Howard Ryan T. , Mayo Michele , Widzowski Dan , Scott David A. , Johannes Jeffrey W. , Lamb Michelle L. , Lawson Deborah , Dry Jonathan R. , Lyne Paul D. , Tate Edward W. , Zinda Michael , Mikule Keith , Fawell Stephen E. , Reimer Corinne , Chen Huawei
Published: March 2023

Abstract
PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced the MPS phenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermore, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together, these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity.
Significance:
These findings describe a new inhibitor of PARP6 and identify a novel function of PARP6 in regulating activation of Chk1 in breast cancer cells.
Data from Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer
Authors: Li Shangze , Fong Ka-wing , Gritsina Galina , Zhang Ali , Zhao Jonathan C. , Kim Jung , Sharp Adam , Yuan Wei , Aversa Caterina , Yang Ximing J. , Nelson Peter S. , Feng Felix Y. , Chinnaiyan Arul M. , de Bono Johann S. , Morrissey Colm , Rettig Matthew B. , Yu Jindan
Published: March 2023

Abstract
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance.
Significance:
These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
Data from YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63–GPX2 Axis and ROS Accumulation
Authors: Huang Hsinyi , Zhang Wenjing , Pan Yafang , Gao Yijun , Deng Lei , Li Fuming , Li Fei , Ma Xueyan , Hou Shenda , Xu Jing , Li Peixue , Li Xiaoxun , Hu Guohong , Li Cheng , Chen Haiquan , Zhang Lei , Ji Hongbin
Published: March 2023

Abstract
Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non–small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769–81. ©2017 AACR.
Data from Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma
Authors: Ma Ding , Liu Senquan , Lal Bachchu , Wei Shuang , Wang Shuyan , Zhan Daqian , Zhang Hao , Lee Richard S. , Gao Peisong , Lopez-Bertoni Hernando , Ying Mingyao , Li Jian Jian , Laterra John , Wilson Mary Ann , Xia Shuli
Published: March 2023

Abstract
Glioblastomas (GBM) are highly infiltrated by myeloid-derived innate immune cells that contribute to the immunosuppressive nature of the brain tumor microenvironment (TME). CD47 has been shown to mediate immune evasion, as the CD47–SIRPα axis prevents phagocytosis of tumor cells by macrophages and other myeloid cells. In this study, we established CD47 homozygous deletion (CD47−/−) in human and mouse GBM cells and investigated the impact of eliminating the "don't eat me" signal on tumor growth and tumor–TME interactions. CD47 knockout (KO) did not significantly alter tumor cell proliferation in vitro but significantly increased phagocytosis of tumor cells by macrophages in cocultures. Compared with CD47 wild-type xenografts, orthotopic xenografts derived from CD47−/− tumor cells grew significantly slower with enhanced tumor cell phagocytosis and increased recruitment of M2-like tumor-associated microglia/macrophages (TAM). CD47 KO increased tumor-associated extracellular matrix protein tenascin C (TNC) in xenografts, which was further examined in vitro. CD47 loss of function upregulated TNC expression in tumor cells via a Notch pathway–mediated mechanism. Depletion of TNC in tumor cells enhanced the growth of CD47−/− xenografts in vivo and decreased the number of TAM. TNC knockdown also inhibited phagocytosis of CD47−/− tumor cells in cocultures. Furthermore, TNC stimulated release of proinflammatory factors including TNFα via a Toll-like receptor 4 and STAT3-dependent mechanism in human macrophage cells. These results reveal a vital role for TNC in immunomodulation in brain tumor biology and demonstrate the prominence of the TME extracellular matrix in affecting the antitumor function of brain innate immune cells.
Significance:
These findings link TNC to CD47-driven phagocytosis and demonstrate that TNC affects the antitumor function of brain TAM, facilitating the development of novel innate immune system–based therapies for brain tumors.
Data from Heterochromatin Protein 1α Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer
Authors: Ci Xinpei , Hao Jun , Dong Xin , Choi Stephen Y. , Xue Hui , Wu Rebecca , Qu Sifeng , Gout Peter W. , Zhang Fang , Haegert Anne M. , Fazli Ladan , Crea Francesco , Ong Christopher J. , Zoubeidi Amina , He Housheng H. , Gleave Martin E. , Collins Colin C. , Lin Dong , Wang Yuzhuo
Published: March 2023

Abstract
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.

Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(10); 2691–704. ©2018 AACR.
Data from HP1γ Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A
Authors: Alam Hunain , Li Na , Dhar Shilpa S. , Wu Sarah J. , Lv Jie , Chen Kaifu , Flores Elsa R. , Baseler Laura , Lee Min Gyu
Published: March 2023

Abstract
Lung adenocarcinoma is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma–promoting histone methylation reader protein show that heterochromatin protein 1γ (HP1γ; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human lung adenocarcinoma, and that high HP1γ mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. In vivo depletion of HP1γ reduced K-RasG12D–driven lung adenocarcinoma and lengthened survival of mice bearing K-RasG12D–induced lung adenocarcinoma. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma cells. HP1γ directly repressed expression of the transcription-repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1γ-depleted lung adenocarcinoma cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high HP1γ mRNA levels in lung adenocarcinoma samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1γ and its reader activity in lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma–promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes.

Significance: Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1γ leads to activation of protumorigenic genes in lung adenocarcinoma. Cancer Res; 78(14); 3834–48. ©2018 AACR.
Data from NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model
Authors: Liu Yan , Li Yuyang , Liu Shengwu , Adeegbe Dennis O. , Christensen Camilla L. , Quinn Max M. , Dries Ruben , Han Shiwei , Buczkowski Kevin , Wang Xiaoen , Chen Ting , Gao Peng , Zhang Hua , Li Fei , Hammerman Peter S. , Bradner James E. , Quayle Steven N. , Wong Kwok-Kin
Published: March 2023

Abstract
Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line–derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.

Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709–17. ©2018 AACR.
Data from Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss
Authors: Murali Bhavna , Ren Qihao , Luo Xianmin , Faget Douglas V. , Wang Chun , Johnson Radia Marie , Gruosso Tina , Flanagan Kevin C. , Fu Yujie , Leahy Kathleen , Alspach Elise , Su Xinming , Ross Michael H. , Burnette Barry , Weilbaecher Katherine N. , Park Morag , Mbalaviele Gabriel , Monahan Joseph B. , Stewart Sheila A.
Published: March 2023

Abstract
The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.

Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618–30. ©2018 AACR.
Data from Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell–like Properties
Authors: Chen Chen , Okita Yukari , Watanabe Yukihide , Abe Fumie , Fikry Muhammad Ali , Ichikawa Yumu , Suzuki Hiroyuki , Shibuya Akira , Kato Mitsuyasu
Published: March 2023

Abstract
Glycoprotein nmb (GPNMB) is a type I transmembrane protein that contributes to the initiation and malignant progression of breast cancer through induction of epithelial–mesenchymal transition (EMT). Although it is known that EMT is associated with not only cancer invasion but also acquisition of cancer stem cell (CSC) properties, the function of GPNMB in this acquisition of CSC properties has yet to be elucidated. To address this issue, we utilized a three-dimensional (3D) sphere culture method to examine the correlation between GPNMB and CSC properties in breast cancer cells. Three-dimensional sphere cultures induced higher expression of CSC genes and EMT-inducing transcription factor (EMT-TF) genes than the 2D monolayer cultures. Three-dimensional culture also induced cell surface expression of GPNMB on limited numbers of cells in the spheres, whereas the 2D cultures did not. Therefore, we isolated cell surface-GPNMBhigh and -GPNMBlow cells from the spheres. Cell surface-GPNMBhigh cells expressed high levels of CSC genes and EMT-TF genes, had significantly higher sphere-forming frequencies than the cell surface-GPNMBlow cells, and showed no detectable levels of proliferation marker genes. Similar results were obtained from transplanted breast tumors. Furthermore, wild-type GPNMB, but not mutant GPNMB (YF), which lacks tumorigenic activity, induced CSC-like properties in breast epithelial cells. These findings suggest that GPNMB is exposed on the surface of dormant breast cancer cells and its activity contributes to the acquisition of stem cell–like properties.

Significance: These findings suggest that cell surface expression of GPNMB could serve as a marker and promising therapeutic target of breast cancer cells with stem cell-like properties. Cancer Res; 78(22); 6424–35. ©2018 AACR.
Data from The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma
Authors: Qiu Mantang , Xia Wenjia , Chen Rui , Wang Siwei , Xu Youtao , Ma Zhifei , Xu Weizhang , Zhang Erbao , Wang Jie , Fang Tian , Hu Jingwen , Dong Gaochao , Yin Rong , Wang Jun , Xu Lin
Published: March 2023

Abstract
Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in lung adenocarcinoma tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of lung adenocarcinoma. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the protumorigenic transcription factor E2F7. Intratumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in patients with lung adenocarcinoma.

Significance: These findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis. Cancer Res; 78(11); 2839–51. ©2018 AACR.