bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Regulation of ERBB2 Receptor by t-DARPP Mediates Trastuzumab Resistance in Human Esophageal Adenocarcinoma
Authors: Hong Jun , Katsha Ahmed , Lu Pengcheng , Shyr Yu , Belkhiri Abbes , El-Rifai Wael
Published: April 2023

Abstract
Esophageal adenocarcinoma (EAC) is an aggressive malignancy with a poor outcome. Although targeting ERBB2 with trastuzumab has been evaluated in clinical trials, the molecular mechanisms of trastuzumab resistance remain uncharacterized in EAC. The dopamine and cyclic AMP-regulated phosphoprotein of MR 32000 (DARPP-32), also known as PPP1R1B, is located together with ERBB2 at the 17q12-q21 amplicon. We evaluated the expression of a transcript variant of DARPP-32 (t-DARPP) and ERBB2 in 141 primary tumors and investigated the role of t-DARPP in trastuzumab resistance using OE19 and OE33 EAC cell models. Overexpression of t-DARPP mRNA was detected in two-thirds of tumors with a correlation between ERBB2 and t-DARPP overexpression levels (r = 0.58, P = 0.003). Cell viability and clonogenic survival assays showed that t-DARPP increased survival by 40% in response to trastuzumab (P < 0.01). The Annexin-V staining and Western blot analysis indicated that t-DARPP effectively abrogated trastuzumab-induced apoptosis, inhibited cleavage of caspase-3, and blocked trastuzumab-induced dephosphorylation of ERBB2 and AKT proteins. The knockdown of endogenous t-DARPP reversed these effects and sensitized cells to trastuzumab (P < 0.01). The cycloheximide-based protein degradation analysis indicated that t-DARPP extended the half-life of ERBB2, explaining the increase in the basal levels of ERBB2, p-ERBB2(Y1248), and p-AKT(S473). Coimmunoprecipitation and Western blot analysis showed that t-DARPP associated with ERBB2 in a protein complex, and interfered with trastuzumab binding to the ERBB2 receptor. Using EAC-xenografted mouse model, t-DARPP enhanced tumor growth and rendered tumors unresponsive to trastuzumab. This study establishes t-DARPP as a mediator of trastuzumab resistance and underscores its potential importance in clinical trials of EAC. Cancer Res; 72(17); 4504–14. ©2012 AACR.
Data from Inactivation of the Dlc1 Gene Cooperates with Downregulation of p15INK4b and p16Ink4a, Leading to Neoplastic Transformation and Poor Prognosis in Human Cancer
Authors: Qian Xiaolan , Durkin Marian E. , Wang Dunrui , Tripathi Brajendra K. , Olson Lyra , Yang Xu-Yu , Vass William C. , Popescu Nicholas C. , Lowy Douglas R.
Published: April 2023

Abstract
The tumor suppressor gene deleted in liver cancer-1 (DLC1), which encodes a protein with strong RhoGAP (GTPase activating protein) activity and weak Cdc42GAP activity, is inactivated in various human malignancies. Following Dlc1 inactivation, mouse embryo fibroblasts (MEF) with a conditional Dlc1 knockout allele reproducibly underwent neoplastic transformation. In addition to inactivation of Dlc1 and increased activity of Rho and Cdc42, transformation depended on the subsequent decreased expression of the Cdk4/6 inhibitors p15Ink4b and p16Ink4a together with increased expression and activation of Cdk4/6. The level of expression of these cell-cycle regulatory genes was relevant to human tumors with low DLC1 expression. Analysis of publicly available annotated datasets of lung and colon cancer with gene expression microarray profiles indicated that, in pairwise comparisons, low DLC1 expression occurred frequently together (P < 0.01) with downregulation of p15Ink4b or p16Ink4a or upregulation of CDK4 or CDK6. In addition, an unfavorable prognosis (P < 0.05) was associated with low DLC1 and low p15Ink4b in lung cancer and colon cancer, low DLC1 and low p16Ink4a in lung cancer, low DLC1 and high CDK4 in lung cancer, and low DLC1 and high CDK6 in colon cancer. Thus, several genes and biochemical activities collaborate with the inactivation of DLC1 to give rise to cell transformation in MEFs, and the identified genes are relevant to human tumors with low DLC1 expression. Cancer Res; 72(22); 5900–11. ©2012 AACR.
Data from PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets
Authors: Scortegagna Marzia , Lau Eric , Zhang Tongwu , Feng Yongmei , Sereduk Chris , Yin Hongwei , De Surya K. , Meeth Katrina , Platt James T. , Langdon Casey G. , Halaban Ruth , Pellecchia Maurizio , Davies Michael A. , Brown Kevin , Stern David F. , Bosenberg Marcus , Ronai Ze'ev A.
Published: April 2023

Abstract
Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. Cancer Res; 75(7); 1399–412. ©2015 AACR.
Data from Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression
Authors: Anz David , Rapp Moritz , Eiber Stephan , Koelzer Viktor H. , Thaler Raffael , Haubner Sascha , Knott Max , Nagel Sarah , Golic Michaela , Wiedemann Gabriela M. , Bauernfeind Franz , Wurzenberger Cornelia , Hornung Veit , Scholz Christoph , Mayr Doris , Rothenfusser Simon , Endres Stefan , Bourquin Carole
Published: April 2023

Abstract
The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I–like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy. Cancer Res; 75(21); 4483–93. ©2015 AACR.
Data from eIF4E Threshold Levels Differ in Governing Normal and Neoplastic Expansion of Mammary Stem and Luminal Progenitor Cells
Authors: Avdulov Svetlana , Herrera Jeremy , Smith Karen , Peterson Mark , Gomez-Garcia Jose R. , Beadnell Thomas C. , Schwertfeger Kathryn L. , Benyumov Alexey O. , Manivel J. Carlos , Li Shunan , Bielinsky Anja-Katrin , Yee Douglas , Bitterman Peter B. , Polunovsky Vitaly A.
Published: April 2023

Abstract
Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self-renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer. Cancer Res; 75(4); 687–97. ©2014 AACR.
Data from Accelerated Tumor Progression in Mice Lacking the ATP Receptor P2X7
Authors: Adinolfi Elena , Capece Marina , Franceschini Alessia , Falzoni Simonetta , Giuliani Anna L. , Rotondo Alessandra , Sarti Alba C. , Bonora Massimo , Syberg Susanne , Corigliano Domenica , Pinton Paolo , Jorgensen Niklas R. , Abelli Luigi , Emionite Laura , Raffaghello Lizzia , Pistoia Vito , Di Virgilio Francesco
Published: April 2023

Abstract
The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. Cancer Res; 75(4); 635–44. ©2014 AACR.
Data from UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas
Authors: Wong Stephen Q. , Waldeck Kelly , Vergara Ismael A. , Schröder Jan , Madore Jason , Wilmott James S. , Colebatch Andrew J. , De Paoli-Iseppi Ricardo , Li Jason , Lupat Richard , Semple Timothy , Arnau Gisela Mir , Fellowes Andrew , Leonard J. Helen , Hruby George , Mann Graham J. , Thompson John F. , Cullinane Carleen , Johnston Meredith , Shackleton Mark , Sandhu Shahneen , Bowtell David D.L. , Johnstone Ricky W. , Fox Stephen B. , McArthur Grant A. , Papenfuss Anthony T. , Scolyer Richard A. , Gill Anthony J. , Hicks Rodney J. , Tothill Richard W.
Published: April 2023

Abstract
Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 5228–34. ©2015 AACR.
Data from MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1
Authors: Lee Jung-Hee , Park Seon-Joo , Jeong Seo-Yeon , Kim Min-Ji , Jun Semo , Lee Hyun-Seo , Chang In-Youb , Lim Sung-Chul , Yoon Sang Pil , Yong Jeongsik , You Ho Jin
Published: April 2023

Abstract
MDC1 is critical component of the DNA damage response (DDR) machinery and orchestrates the ensuring assembly of the DDR protein at the DNA damage sites, and therefore loss of MDC1 results in genomic instability and tumorigenicity. However, the molecular mechanisms controlling MDC1 expression are currently unknown. Here, we show that miR-22 inhibits MDC1 translation via direct binding to its 3′ untranslated region, leading to impaired DNA damage repair and genomic instability. We demonstrated that activated Akt1 and senescence hinder DDR function of MDC1 by upregulating endogenous miR-22. After overexpression of constitutively active Akt1, homologous recombination was inhibited by miR-22–mediated MDC1 repression. In addition, during replicative senescence and stress-induced premature senescence, MDC1 was downregulated by upregulating miR-22 and thereby accumulating DNA damage. Our results demonstrate a central role of miR-22 in the physiologic regulation of MDC1-dependent DDR and suggest a molecular mechanism for how aberrant Akt1 activation and senescence lead to increased genomic instability, fostering an environment that promotes tumorigenesis. Cancer Res; 75(7); 1298–310. ©2015 AACR.
Data from CRLX101, a Nanoparticle–Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α
Authors: Tian Xi , Nguyen Minh , Foote Henry P. , Caster Joseph M. , Roche Kyle C. , Peters Christian G. , Wu Pauline , Jayaraman Lata , Garmey Edward G. , Tepper Joel E. , Eliasof Scott , Wang Andrew Z.
Published: April 2023

Abstract
Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle–drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112–22. ©2016 AACR.
Data from Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma
Authors: Rao Shuyun , Cai Kathy Q. , Stadanlick Jason E. , Greenberg-Kushnir Noa , Solanki-Patel Nehal , Lee Sang-Yun , Fahl Shawn P. , Testa Joseph R. , Wiest David L.
Published: April 2023

Abstract
Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one Rpl22 allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of Rpl22 restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an Rpl22−/− background developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22+/+ control mice. But, unlike Rpl22+/+ or Rpl22+/− tumors, Rpl22−/− lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in the Rpl22−/− lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, reexpression of S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity in vitro. The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 reexpression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of Rpl22 promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus. Cancer Res; 76(11); 3387–96. ©2016 AACR.
Data from TMEM2 Is a SOX4-Regulated Gene That Mediates Metastatic Migration and Invasion in Breast Cancer
Authors: Lee Hyeseung , Goodarzi Hani , Tavazoie Sohail F. , Alarcón Claudio R.
Published: April 2023

Abstract
The developmental transcription factor SOX4 contributes to the metastatic spread of multiple solid cancer types, but its direct target genes that mediate cancer progression are not well defined. Using a systematic molecular and genomic approach, we identified the TMEM2 transmembrane protein gene as a direct transcriptional target of SOX4. TMEM2 was transcriptionally activated by SOX4 in breast cancer cells where, like SOX4, TMEM2 was found to mediate proinvasive and promigratory effects. Similarly, TMEM2 was sufficient to promote metastatic colonization of breast cancer cells and its expression in primary breast tumors associated with a higher likelihood of metastatic relapse. Given earlier evidence that genetic inactivation of SOX4 or TMEM2 yield similar defects in cardiac development, our findings lead us to propose that TMEM2 may not only mediate the pathologic effects of SOX4 on cancer progression but also potentially its contributions to embryonic development. Cancer Res; 76(17); 4994–5005. ©2016 AACR.
Data from Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205
Authors: Hirata Hiroshi , Hinoda Yuji , Shahryari Varahram , Deng Guoren , Nakajima Koichi , Tabatabai Z. Laura , Ishii Nobuhisa , Dahiya Rajvir
Published: April 2023

Abstract
Recently, long noncoding RNAs (lncRNA) have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). In this study, we investigated the contributions of the lncRNA MALAT1 in RCC with a specific focus on its transcriptional regulation and its interactions with Ezh2 and miR-205. We found that MALAT1 expression was higher in human RCC tissues, where it was associated with reduced patient survival. MALAT1 silencing decreased RCC cell proliferation and invasion and increased apoptosis. Mechanistic investigations showed that MALAT1 was transcriptionally activated by c-Fos and that it interacted with Ezh2. After MALAT1 silencing, E-cadherin expression was increased, whereas β-catenin expression was decreased through Ezh2. Reciprocal interaction between MALAT1 and miR-205 was also observed. Lastly, MALAT1 bound Ezh2 and oncogenesis facilitated by MALAT1 was inhibited by Ezh2 depletion, thereby blocking epithelial–mesenchymal transition via E-cadherin recovery and β-catenin downregulation. Overall, our findings illuminate how overexpression of MALAT1 confers an oncogenic function in RCC that may offer a novel theranostic marker in this disease. Cancer Res; 75(7); 1322–31. ©2015 AACR.
Data from An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer
Authors: Olow Aleksandra , Chen Zhongzhong , Niedner R. Hannes , Wolf Denise M. , Yau Christina , Pankov Aleksandr , Lee Evelyn Pei Rong , Brown-Swigart Lamorna , van ‘t Veer Laura J. , Coppé Jean-Philippe
Published: April 2023

Abstract
Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR.
Data from Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling
Authors: Catalano Veronica , Dentice Monica , Ambrosio Raffaele , Luongo Cristina , Carollo Rosachiara , Benfante Antonina , Todaro Matilde , Stassi Giorgio , Salvatore Domenico
Published: April 2023

Abstract
Thyroid hormone is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSC). Thyroid hormone concentrations in the blood are stable, but the action of the deiodinases (D2–D3) provides cell-specific regulation of thyroid hormone activity. Deregulation of deiodinase function and thyroid hormone status has been implicated in tumorigenesis. Therefore, we investigated the role of thyroid hormone metabolism and signaling in colorectal CSCs (CR-CSC), where deiodinases control cell division and chemosensitivity. We found that increased intracellular thyroid hormone concentration through D3 depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling. Collectively, our findings highlight a cell-autonomous metabolic mechanism by which CR-CSCs exploit thyroid hormone signaling to facilitate their self-renewal potential and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression. Cancer Res; 76(5); 1237–44. ©2015 AACR.
Data from Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients
Authors: Osman Abdullah A. , Neskey David M. , Katsonis Panagiotis , Patel Ameeta A. , Ward Alexandra M. , Hsu Teng-Kuei , Hicks Stephanie C. , McDonald Thomas O. , Ow Thomas J. , Alves Marcus Ortega , Pickering Curtis R. , Skinner Heath D. , Zhao Mei , Sturgis Eric M. , Kies Merrill S. , El-Naggar Adel , Perrone Federica , Licitra Lisa , Bossi Paolo , Kimmel Marek , Frederick Mitchell J. , Lichtarge Olivier , Myers Jeffrey N.
Published: April 2023

Abstract
TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high-risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC. Cancer Res; 75(7); 1205–15. ©2015 AACR.
Data from S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
Authors: Rizza Salvatore , Montagna Costanza , Cardaci Simone , Maiani Emiliano , Di Giacomo Giuseppina , Sanchez-Quiles Virginia , Blagoev Blagoy , Rasola Andrea , De Zio Daniela , Stamler Jonathan S. , Cecconi Francesco , Filomeni Giuseppe
Published: April 2023

Abstract
S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys501 in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170–82. ©2016 AACR.
Data from Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer
Authors: Lastwika Kristin J. , Wilson Willie , Li Qing Kay , Norris Jeffrey , Xu Haiying , Ghazarian Sharon R. , Kitagawa Hiroshi , Kawabata Shigeru , Taube Janis M. , Yao Sheng , Liu Linda N. , Gills Joell J. , Dennis Phillip A.
Published: April 2023

Abstract
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 227–38. ©2015 AACR.
Data from Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis
Authors: Housseau Franck , Wu Shaoguang , Wick Elizabeth C. , Fan Hongni , Wu Xinqun , Llosa Nicolas J. , Smith Kellie N. , Tam Ada , Ganguly Sudipto , Wanyiri Jane W. , Iyadorai Thevambiga , Malik Ausama A. , Roslani April C. , Vadivelu Jamunarani S. , Van Meerbeke Sara , Huso David L. , Pardoll Drew M. , Sears Cynthia L.
Published: April 2023

Abstract
IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing MinApc+/− mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4+ T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115–24. ©2016 AACR.
Data from PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers
Authors: Labbé David P. , Uetani Noriko , Vinette Valérie , Lessard Laurent , Aubry Isabelle , Migon Eva , Sirois Jacinthe , Haigh Jody J. , Bégin Louis R. , Trotman Lloyd C. , Paquet Marilène , Tremblay Michel L.
Published: April 2023

Abstract
Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten−/−Ptpn1−/− mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate prostate cancer, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten−/− mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer. Cancer Res; 76(11); 3130–5. ©2016 AACR.
Data from Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression
Authors: Botla Sandeep K. , Savant Soniya , Jandaghi Pouria , Bauer Andrea S. , Mücke Oliver , Moskalev Evgeny A. , Neoptolemos John P. , Costello Eithne , Greenhalf William , Scarpa Aldo , Gaida Matthias M. , Büchler Markus W. , Strobel Oliver , Hackert Thilo , Giese Nathalia A. , Augustin Hellmut G. , Hoheisel Jörg D.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR.
Data from A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis
Authors: Fang Liang , Zhu Qionghua , Neuenschwander Martin , Specker Edgar , Wulf-Goldenberg Annika , Weis William I. , von Kries Jens P. , Birchmeier Walter
Published: April 2023

Abstract
Wnt/β-catenin signaling is a highly conserved pathway essential for embryogenesis and tissue homeostasis. However, deregulation of this pathway can initiate and promote human malignancies, especially of the colon and head and neck. Therefore, Wnt/β-catenin signaling represents an attractive target for cancer therapy. We performed high-throughput screening using AlphaScreen and ELISA techniques to identify small molecules that disrupt the critical interaction between β-catenin and the transcription factor TCF4 required for signal transduction. We found that compound LF3, a 4-thioureido-benzenesulfonamide derivative, robustly inhibited this interaction. Biochemical assays revealed clues that the core structure of LF3 was essential for inhibition. LF3 inhibited Wnt/β-catenin signals in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. LF3 also suppressed features of cancer cells related to Wnt signaling, including high cell motility, cell-cycle progression, and the overexpression of Wnt target genes. However, LF3 did not cause cell death or interfere with cadherin-mediated cell–cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under nonadherent conditions. Finally, LF3 reduced tumor growth and induced differentiation in a mouse xenograft model of colon cancer. Collectively, our results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy. Cancer Res; 76(4); 891–901. ©2015 AACR.
Data from Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies
Authors: Adams Clare M. , Hiebert Scott W. , Eischen Christine M.
Published: April 2023

Abstract
Alterations in the expression or function of histone deacetylases (HDAC) contribute to the development and progression of hematologic malignancies. Consequently, the development and implementation of HDAC inhibitors has proven to be therapeutically beneficial, particularly for hematologic malignancies. However, the molecular mechanisms by which HDAC inhibition (HDACi) induces tumor cell death remain unresolved. Here, we investigated the effects of HDACi in Myc-driven B-cell lymphoma and five other hematopoietic malignancies. We determined that Myc-mediated transcriptional repression of the miR-15 and let-7 families in malignant cells was relieved upon HDACi, and Myc was required for their upregulation. The miR-15 and let-7 families then targeted and downregulated the antiapoptotic genes Bcl-2 and Bcl-xL, respectively, to induce HDACi-mediated apoptosis. Notably, Myc also transcriptionally upregulated these miRNA in untransformed cells, indicating that this Myc-induced miRNA-mediated apoptotic pathway is suppressed in malignant cells, but becomes reactivated upon HDACi. Taken together, our results reveal a previously unknown mechanism by which Myc induces apoptosis independent of the p53 pathway and as a response to HDACi in malignant hematopoietic cells. Cancer Res; 76(3); 736–48. ©2015 AACR.
Data from Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells
Authors: Mittal Deepak , Caramia Franco , Michiels Stefan , Joensuu Heikki , Kellokumpu-Lehtinen Pirkko-Liisa , Sotiriou Christos , Loi Sherene , Smyth Mark J.
Published: April 2023

Abstract
The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2+ breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8+ T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4+ T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer Res; 76(2); 264–74. ©2016 AACR.
Data from Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases
Authors: Isozaki Hideko , Ichihara Eiki , Takigawa Nagio , Ohashi Kadoaki , Ochi Nobuaki , Yasugi Masayuki , Ninomiya Takashi , Yamane Hiromichi , Hotta Katsuyuki , Sakai Katsuya , Matsumoto Kunio , Hosokawa Shinobu , Bessho Akihiro , Sendo Toshiaki , Tanimoto Mitsune , Kiura Katsuyuki
Published: April 2023

Abstract
Crizotinib is the standard of care for advanced non–small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. Cancer Res; 76(6); 1506–16. ©2015 AACR.
Data from Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem–like Cells
Authors: Giraud Julie , Failla Laura M. , Pascussi Jean-Marc , Lagerqvist Ebba L. , Ollier Jérémy , Finetti Pascal , Bertucci François , Ya Chu , Gasmi Imène , Bourgaux Jean-François , Prudhomme Michel , Mazard Thibault , Ait-Arsa Imade , Houhou Leila , Birnbaum Daniel , Pélegrin André , Vincent Charles , Ryall James G. , Joubert Dominique , Pannequin Julie , Hollande Frédéric
Published: April 2023

Abstract
Subpopulations of cancer stem–like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference–mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDHhigh cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDHhigh CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618–28. ©2016 AACR.
Data from Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1
Authors: Mazzieri Roberta , Pietrogrande Giovanni , Gerasi Laura , Gandelli Alessandro , Colombo Piergiuseppe , Moi Davide , Brombin Chiara , Ambrosi Alessandro , Danese Silvio , Mignatti Paolo , Blasi Francesco , D'Alessio Silvia
Published: April 2023

Abstract
The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development. Cancer Res; 75(22); 4895–909. ©2015 AACR.
Data from Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus
Authors: Camp Nicola J. , Lin Wei-Yu , Bigelow Alex , Burghel George J. , Mosbruger Timothy L. , Parry Marina A. , Waller Rosalie G. , Rigas Sushilaben H. , Tai Pei-Yi , Berrett Kristofer , Rajamanickam Venkatesh , Cosby Rachel , Brock Ian W. , Jones Brandt , Connley Dan , Sargent Robert , Wang Guoying , Factor Rachel E. , Bernard Philip S. , Cannon-Albright Lisa , Knight Stacey , Abo Ryan , Werner Theresa L. , Reed Malcolm W.R. , Gertz Jason , Cox Angela
Published: April 2023

Abstract
The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916–25. ©2016 AACR.