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Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses.
Singh K, Coburn LA, Asim M, Barry DP, Allaman MM, Shi C, Washington MK, Luis PB, Schneider C, Delgado AG, Piazuelo MB, Cleveland JL, Gobert AP, Wilson KT
(2018) Cancer Res :
Show Abstract · Added June 15, 2018
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis and restricts M1 macrophage activation in gastrointestinal (GI) infections. However, the role of macrophage ODC in colonic epithelial-driven inflammation is unknown. Here we investigate cell-specific effects of ODC in colitis and colitis-associated carcinogenesis (CAC). Human colonic macrophages expressed increased ODC levels in active ulcerative colitis and Crohn's disease, colitis-associated dysplasia, and CAC. Mice lacking Odc in myeloid cells (Odc∆mye mice) that were treated with dextran sulfate sodium (DSS) exhibited improved survival, body weight, and colon length and reduced histologic injury versus control mice. In contrast, gastrointestinal epithelial-specific Odc knockout had no effect on clinical parameters. Despite reduced histologic damage, colitis tissues of Odc∆mye mice had increased levels of multiple pro-inflammatory cytokines and chemokines and enhanced expression of M1, but not M2 markers. In the azoxymethane (AOM)-DSS model of CAC, Odc∆mye mice had reduced tumor number, burden, and high-grade dysplasia. Tumors from Odc∆mye mice had increased M1, but not M2 macrophages. Increased levels of histone 3, lysine 9 acetylation (H3K9ac), a marker of open chromatin, were manifest in tumor macrophages of Odc∆mye mice, consistent with our findings that macrophage ODC affects histone modifications that upregulate M1 gene transcription during GI infections. These findings support the concept that macrophage ODC augments epithelial injury-associated colitis and CAC by impairing the M1 responses that stimulate epithelial repair, antimicrobial defense, and anti-tumoral immunity. They also suggest that macrophage ODC is an important target for colon cancer chemoprevention.
Copyright ©2018, American Association for Cancer Research.
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Selective mTORC2 inhibitor therapeutically blocks breast cancer cell growth and survival.
Werfel TA, Wang S, Jackson MA, Kavanaugh TE, Morrison Joly M, Lee L, Hicks DJ, Sanchez V, Gonzalez-Ericsson PI, Kilchrist KV, Dimobi SC, Sarett SM, Brantley-Sieders DM, Cook RS, Duvall C
(2018) Cancer Res :
Show Abstract · Added March 14, 2018
Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intra-tumoral and intra-venous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a TNBC model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.
Copyright ©2018, American Association for Cancer Research.
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Loss of ACVRIB leads to increased squamous cell carcinoma aggressiveness through alterations in cell-cell and cell-matrix adhesion proteins.
Loomans HA, Arnold SA, Hebron K, Taylor CJ, Zijlstra A, Andl CD
(2017) Am J Cancer Res 7: 2422-2437
Show Abstract · Added March 22, 2018
Squamous cell carcinomas of the head and neck (HNSCC) and esophagus (ESCC) pose a global public health issue due to high mortality rates. Unfortunately, little progress has been made in improving patient outcomes. This is partially a result of a lack of understanding the mechanisms that drive SCC progression. Recently, Activin A signaling has been implicated in a number of cancers, yet the role of this pathway in SCC remains poorly understood. We have previously discovered that the Activin A ligand acts as a tumor suppressor when epithelial Activin receptor type IB (ACVRIB) is intact; however, this effect is lost upon ACVRIB downregulation. In the present study, we investigated the function of ACVRIB in the regulation of SCC. Using CRISPR/Cas9-mediated ACVRIB-knockout and knockdown using siRNA, we found an increased capacity to proliferate, migrate, and invade upon ACRIB loss, as ACVRIB-KO cells exhibited an altered cytoskeleton and aberrant expression of E-cadherin and integrins. Based on chemical inhibitor studies, our data suggests that these effects are mediated through ACVRIB-independent signaling via downstream activation of Smad1/5/8 and MEK/ERK. Overall, we present a novel mechanism of SCC progression upon ACVRIB loss by showing that Activin A can transduce a signal in the absence of ACVRIB.
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C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3KInhibitors.
Croessmann S, Sheehan JH, Lee KM, Sliwoski G, He J, Nagy R, Riddle D, Mayer IA, Balko JM, Lanman R, Miller VA, Cantley LC, Meiler J, Arteaga CL
(2018) Clin Cancer Res 24: 1426-1435
Show Abstract · Added March 14, 2018
We describe herein a novel P447_L455 deletion in the C2 domain ofin a patient with an ERbreast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Althoughdeletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110α function.A computational structural model ofin complex with the p85 regulatory subunit and MCF10A cells expressingandwere used to understand the phenotype of C2 domain deletions.Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressingC2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.C2 domain deletions ingenerate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors..
©2017 American Association for Cancer Research.
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The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2).
Aisner DL, Sholl LM, Berry LD, Rossi MR, Chen H, Fujimoto J, Moreira AL, Ramalingam SS, Villaruz LC, Otterson GA, Haura E, Politi K, Glisson B, Cetnar J, Garon EB, Schiller J, Waqar SN, Sequist LV, Brahmer J, Shyr Y, Kugler K, Wistuba II, Johnson BE, Minna JD, Kris MG, Bunn PA, Kwiatkowski DJ, LCMC2 investigators
(2018) Clin Cancer Res 24: 1038-1047
Show Abstract · Added April 3, 2018
Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.The use of targeted therapies in patients withorp.V600E mutations,, orrearrangements, oramplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in//, when compared with 75 never smokers with the same alterations. In addition, coexistingmutations were associated with shorter survival among patients with, oralterations.Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment..
©2017 American Association for Cancer Research.
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T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.
Josefsson SE, Huse K, Kolstad A, Beiske K, Pende D, Steen CB, Inderberg EM, Lingjærde OC, Østenstad B, Smeland EB, Levy R, Irish JM, Myklebust JH
(2018) Clin Cancer Res 24: 870-881
Show Abstract · Added December 15, 2017
T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored uponculture. The costimulatory receptor CD226 was downregulated in TIGITcompared with TIGITCD8 FL T cells, further skewing the balance toward immunosuppression.TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients..
©2017 American Association for Cancer Research.
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ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.
Williams MM, Vaught DB, Joly MM, Hicks DJ, Sanchez V, Owens P, Rahman B, Elion DL, Balko JM, Cook RS
(2017) Breast Cancer Res 19: 105
Show Abstract · Added March 14, 2018
BACKGROUND - During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland.
METHODS - We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs).
RESULTS - Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3dams weighed significantly less when compared to litters nursed by ErbB3dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype.
CONCLUSIONS - These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation.
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Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ERBreast Cancer.
Formisano L, Stauffer KM, Young CD, Bhola NE, Guerrero-Zotano AL, Jansen VM, Estrada MM, Hutchinson KE, Giltnane JM, Schwarz LJ, Lu Y, Balko JM, Deas O, Cairo S, Judde JG, Mayer IA, Sanders M, Dugger TC, Bianco R, Stricker T, Arteaga CL
(2017) Clin Cancer Res 23: 6138-6150
Show Abstract · Added March 14, 2018
amplification occurs in approximately 15% of estrogen receptor-positive (ER) human breast cancers. We investigated mechanisms by whichamplification confers antiestrogen resistance to ERbreast cancer.ERtumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER/-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR.ER/-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER/amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER/-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER/amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.sThese data suggest the ERα pathway remains active in estrogen-deprived ER/-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists..
©2017 American Association for Cancer Research.
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Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Dolan ME, El Charif O, Wheeler HE, Gamazon ER, Ardeshir-Rouhani-Fard S, Monahan P, Feldman DR, Hamilton RJ, Vaughn DJ, Beard CJ, Fung C, Kim J, Fossa SD, Hertz DL, Mushiroda T, Kubo M, Einhorn LH, Cox NJ, Travis LB, Platinum Study Group
(2017) Clin Cancer Res 23: 5757-5768
Show Abstract · Added October 27, 2017
Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06;= 2 × 10), smoking (OR, 1.54;= 0.004), excess drinking (OR, 1.83;= 0.007), and hypertension (OR, 1.61;= 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56;= 2.6 × 10) and weight gain adjusted for years since treatment (OR per Δkg/m, 1.05;= 0.004). PrediXcan identified lower expressions ofandand higherexpression as associated with CisIPN (value for each < 5 × 10) with replication ofmeeting significance criteria (Fisher combined= 0.0089).CisIPN is associated with age, modifiable risk factors, and genetically determined expression level ofFurther study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN..
©2017 American Association for Cancer Research.
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IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.
Wang YA, Sun Y, Palmer J, Solomides C, Huang LC, Shyr Y, Dicker AP, Lu B
(2017) Mol Cancer Res 15: 896-904
Show Abstract · Added April 18, 2017
Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whetherdeficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an-null mouse model was generated in combination withto compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression.-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in amouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin responseand confirmed that the suppression is in part by blocking IGF1 signaling.These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy..
©2017 American Association for Cancer Research.
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