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  • PKC{varepsilon} Controls Mitotic Progression by Regulating Centrosome
           Migration and Mitotic Spindle Assembly

    • Authors: Martini, S; Soliman, T, Gobbi, G, Mirandola, P, Carubbi, C, Masselli, E, Pozzi, G, Parker, P. J, Vitale, M.
      Pages: 3 - 15
      Abstract: To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKC) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase–anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKC in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKC controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKC dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a characteristic of many transformed cells. Thus, PKC appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKC as a potential cancer therapeutic target.Implications: The close relationship between PKC dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a hallmark of transformed cells, strongly suggests PKC as a therapeutic target in cancer. Mol Cancer Res; 16(1); 3–15. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0244
      Issue No: Vol. 16, No. 1 (2018)
  • Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by

    • Authors: Chu, T. L. H; Connell, M, Zhou, L, He, Z, Won, J, Chen, H, Rahavi, S. M. R, Mohan, P, Nemirovsky, O, Fotovati, A, Pujana, M. A, Reid, G. S. D, Nielsen, T. O, Pante, N, Maxwell, C. A.
      Pages: 16 - 31
      Abstract: Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator. Cell migration occurred with an elevated velocity and directionality during the S–G2-phase of the cell cycle, and cells in this phase possess front-polarized centrosomes with augmented microtubule nucleation capacity. Inhibition of Aurora kinase-A (AURKA/Aurora-A) dampens these phenotypes without altering cell-cycle progression. During G2-phase, the level of phosphorylated Aurora-A at centrosomes is reduced in hyaluronan-mediated motility receptor (HMMR)-silenced cells as is the nuclear transport of TPX2, an Aurora-A–activating protein. TPX2 nuclear transport depends upon HMMR-T703, which releases TPX2 from a complex with importin-α (KPNA2) at the nuclear envelope. Finally, the abundance of phosphorylated HMMR-T703, a substrate for Aurora-A, predicts breast cancer–specific survival and relapse-free survival in patients with estrogen receptor (ER)–negative (n = 941), triple-negative (TNBC) phenotype (n = 538), or basal-like subtype (n = 293) breast cancers, but not in those patients with ER-positive breast cancer (n = 2,218). Together, these data demonstrate an Aurora-A/TPX2/HMMR molecular axis that intersects cell-cycle progression and cell migration.Implications: Tumor cell engraftment, migration, and cell-cycle progression share common regulation of the microtubule cytoskeleton through the Aurora-A/TPX2/HMMR axis, which has the potential to influence the survival of patients with ER-negative breast tumors. Mol Cancer Res; 16(1); 16–31. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0417
      Issue No: Vol. 16, No. 1 (2018)
  • Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is
           Regulated by MNK1 and mRNA Translation

    • Authors: Bell, J. B; Eckerdt, F, Dhruv, H. D, Finlay, D, Peng, S, Kim, S, Kroczynska, B, Beauchamp, E. M, Alley, K, Clymer, J, Goldman, S, Cheng, S.-Y, James, C. D, Nakano, I, Horbinski, C, Mazar, A. P, Vuori, K, Kumthekar, P, Raizer, J, Berens, M. E, Platanias, L. C.
      Pages: 32 - 46
      Abstract: Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood–brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1–eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival.Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32–46. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0397
      Issue No: Vol. 16, No. 1 (2018)
  • Personalized siRNA-Nanoparticle Systemic Therapy using Metastatic Lymph
           Node Specimens Obtained with EBUS-TBNA in Lung Cancer

    • Authors: Kato, T; Lee, D, Huang, H, Cruz, W, Ujiie, H, Fujino, K, Wada, H, Patel, P, Hu, H.-p, Hirohashi, K, Nakajima, T, Sato, M, Kaji, M, Kaga, K, Matsui, Y, Chen, J, Zheng, G, Yasufuku, K.
      Pages: 47 - 57
      Abstract: Inhibiting specific gene expression with siRNA provides a new therapeutic strategy to tackle many diseases at the molecular level. Recent strategies called high-density lipoprotein (HDL)-mimicking peptide-phospholipid nanoscaffold (HPPS) nanoparticles have been used to induce siRNAs-targeted delivery to scavenger receptor class B type I receptor (SCARB1)-expressing cancer cells with high efficiency. Here, eight ideal therapeutic target genes were identified for advanced lung cancer throughout the screenings using endobronchial ultrasonography–guided transbronchial needle aspiration (EBUS-TBNA) and the establishment of a personalized siRNA-nanoparticle therapy. The relevance of these genes was evaluated by means of siRNA experiments in cancer cell growth. To establish a therapeutic model, kinesin family member-11 (KIF11) was selected as a target gene. A total of 356 lung cancers were analyzed immunohistochemically for its clinicopathologic significance. The antitumor effect of HPPS-conjugated siRNA was evaluated in vivo using xenograft tumor models. Inhibition of gene expression for these targets effectively suppressed lung cancer cell growth. SCARB1 was highly expressed in a subset of tumors from the lung large-cell carcinoma (LCC) and small-cell lung cancer (SCLC) patients. High-level KIF11 expression was identified as an independent prognostic factor in LCC and squamous cell carcinoma (SqCC) patients. Finally, a conjugate of siRNA against KIF11 and HPPS nanoparticles induced downregulation of KIF11 expression and mediated dramatic inhibition of tumor growth in vivo.Implications: This approach showed delivering personalized cancer-specific siRNAs via the appropriate nanocarrier may be a novel therapeutic option for patients with advanced lung cancer. Mol Cancer Res; 16(1); 47–57. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-16-0341
      Issue No: Vol. 16, No. 1 (2018)
  • Heat Shock Protein 70 (Hsp70) Suppresses RIP1-Dependent Apoptotic and
           Necroptotic Cascades

    • Authors: Srinivasan, S. R; Cesa, L. C, Li, X, Julien, O, Zhuang, M, Shao, H, Chung, J, Maillard, I, Wells, J. A, Duckett, C. S, Gestwicki, J. E.
      Pages: 58 - 68
      Abstract: Hsp70 is a molecular chaperone that binds to "client" proteins and protects them from protein degradation. Hsp70 is essential for the survival of many cancer cells, but it is not yet clear which of its clients are involved. Using structurally distinct chemical inhibitors, we found that many of the well-known clients of the related chaperone, Hsp90, are not strikingly responsive to Hsp70 inhibition. Rather, Hsp70 appeared to be important for the stability of the RIP1 (RIPK1) regulators: cIAP1/2 (BIRC1 and BIRC3), XIAP, and cFLIPS/L (CFLAR). These results suggest that Hsp70 limits apoptosis and necroptosis pathways downstream of RIP1. Consistent with this model, MDA-MB-231 breast cancer cells treated with Hsp70 inhibitors underwent apoptosis, while cotreatment with z-VAD.fmk switched the cell death pathway to necroptosis. In addition, cell death in response to Hsp70 inhibitors was strongly suppressed by RIP1 knockdown or inhibitors. Thus, these data indicate that Hsp70 plays a previously unrecognized and important role in suppressing RIP1 activity.Implications: These findings clarify the role of Hsp70 in prosurvival signaling and suggest IAPs as potential new biomarkers for Hsp70 inhibition. Mol Cancer Res; 16(1); 58–68. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0408
      Issue No: Vol. 16, No. 1 (2018)
  • Functional Impact of Chromatin Remodeling Gene Mutations and Predictive
           Signature for Therapeutic Response in Bladder Cancer

    • Authors: Duex, J. E; Swain, K. E, Dancik, G. M, Paucek, R. D, Owens, C, Churchill, M. E. A, Theodorescu, D.
      Pages: 69 - 77
      Abstract: Urothelial carcinoma accounts for most of the bladder cancer cases. Using next-generation sequencing (NGS) technology, we found that a significant percentage (83%) of tumors had mutations in chromatin-remodeling genes. Here, we examined the functional relevance of mutations in two chromatin-remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost one-third of patients. Interestingly, almost half of missense mutations cluster in the histone-acetyltransferase (HAT) domain of EP300/CREBBP. This domain catalyzes the transfer of an acetyl group to target molecules such as histones, thereby regulating chromatin dynamics. Thus, patients with EP300 or CREBBP mutations may have alterations in the ability of the corresponding proteins to modify histone proteins and control transcriptional profiles. In fact, it was determined that many of the missense HAT mutations in EP300 (64%) and CREBBP (78%) were HAT-inactivating. These inactivating mutations also correlated with invasive disease in patients. Strikingly, the prediction software Mutation Assessor accurately predicted the functional consequences of each HAT missense mutation. Finally, a gene expression signature was developed that associated with loss of HAT activity and that this signature was associated with more aggressive cancer in four patient datasets. Further supporting the notion that this score accurately reflects HAT activity, we found it is responsive to treatment of cancer cells to mocetinostat, a histone deacetylase (HDAC) inhibitor.Implication: This study provides a rationale for targeted sequencing of EP300 and CREBBP and use of a gene profiling signature for predicting therapeutic response in patients. Mol Cancer Res; 16(1); 69–77. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0260
      Issue No: Vol. 16, No. 1 (2018)
  • Divergent Activity of the Pseudogene PTENP1 in ER-Positive and Negative
           Breast Cancer

    • Authors: Yndestad, S; Austreid, E, Skaftnesmo, K. O, Lonning, P. E, Eikesdal, H. P.
      Pages: 78 - 89
      Abstract: Transcripts derived from the PTEN pseudogene (PTENP1) function as decoys to adsorb miRNAs targeting the PTEN tumor suppressor for degradation, and PTENP1 upregulation is known to inhibit growth in preclinical cancer models. Here, PTENP1 3'UTR transduction influences PTEN, AKT/mTOR signaling, and tumor progression in estrogen receptor (ER)-positive and -negative breast cancer cells. PTENP1 upregulation decreases PTEN gene expression in the ER-positive MCF7 and T47D human breast carcinoma cells and accelerates MCF7 tumor growth in vivo. Of note, PTENP1 transduction significantly decreases ERα (ESR1) mRNA and protein levels in MCF7 xenografts with a concomitant increase in hsa-miR-26a, a miRNA known to target ESR1. In the ER-negative MDA-MB-231 and C3HBA breast cancer cells, upregulation of PTENP1 increases PTEN gene expression with no influence on hsa-miR-26a, ESR1, or ERα expression. While PTENP1 transduction did not influence the growth rate of human MDA-MB-231 xenografts, PTENP1 upregulation profoundly reduces its metastatic propensity. Furthermore, PTENP1 significantly inhibits the growth rate of ER-negative C3HBA murine breast cancer xenografts. PTENP1 transduction had no influence on doxorubicin cytotoxicity in ER-positive MCF7 cells but an increase in doxorubicin sensitivity was observed in the ER-negative MDA-MB-231 cells. In summary, while PTENP1 upregulation decreased PTEN transcript levels and stimulated the growth of ER-positive breast cancers, increased PTEN transcript levels and inhibited tumor progression was observed in the ER-negative cells.Implications: This report highlights the profound biological activity of PTENP1 in breast cancer, which is dictated by the hormone receptor status. Mol Cancer Res; 16(1); 78–89. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0207
      Issue No: Vol. 16, No. 1 (2018)
  • HPV Integration in HNSCC Correlates with Survival Outcomes, Immune
           Response Signatures, and Candidate Drivers

    • Authors: Koneva, L. A; Zhang, Y, Virani, S, Hall, P. B, McHugh, J. B, Chepeha, D. B, Wolf, G. T, Carey, T. E, Rozek, L. S, Sartor, M. A.
      Pages: 90 - 102
      Abstract: The incidence of human papillomavirus (HPV)–related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV+ HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors (n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1). A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV– patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4+, CD3+, regulatory, CD8+ T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation.Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90–102. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0153
      Issue No: Vol. 16, No. 1 (2018)
  • A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM
           Stem Cells

    • Authors: Kulkarni, S; Goel-Bhattacharya, S, Sengupta, S, Cochran, B. H.
      Pages: 103 - 114
      Abstract: Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11, and RAN, the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival.Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103–14. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0146
      Issue No: Vol. 16, No. 1 (2018)
  • Genomic Gain of 16p13.3 in Prostate Cancer Predicts Poor Clinical Outcome
           after Surgical Intervention

    • Authors: Bramhecha, Y. M; Guerard, K.-P, Rouzbeh, S, Scarlata, E, Brimo, F, Chevalier, S, Hamel, L, Dragomir, A, Aprikian, A. G, Lapointe, J.
      Pages: 115 - 123
      Abstract: Identifying tumors with high metastatic potential is key to improving the clinical management of prostate cancer. Recently, we characterized a chromosome 16p13.3 gain frequently observed in prostate cancer metastases and now demonstrate the prognostic value of this genomic alteration in surgically treated prostate cancer. Dual-color FISH was used to detect 16p13.3 gain on a human tissue microarray representing 304 primary radical prostatectomy (RP) cases with clinical follow-up data. The results were validated in an external dataset. The 16p13.3 gain was detected in 42% (113/267) of the specimens scorable by FISH and was significantly associated with clinicopathologic features of aggressive prostate cancer, including high preoperative PSA (P = 0.03) levels, high Gleason score (GS, P < 0.0001), advanced pathologic tumor stage (P < 0.0001), and positive surgical margins (P = 0.009). The 16p13.3 gain predicted biochemical recurrence (BCR) in the overall cohort (log-rank P = 0.0005), and in subsets of patients with PSA ≤10 or GS ≤7 (log-rank P = 0.02 and P = 0.006, respectively). Moreover, combining the 16p13.3 gain status with standard prognostic markers improved BCR risk stratification and identified a subgroup of patients with high probability of recurrence. The 16p13.3 gain status was also associated with an increased risk of developing distant metastases (log-rank P = 0.03) further substantiating its role in prostate cancer progression.Implications: This study demonstrates the prognostic significance of the 16p13.3 genomic gain in primary prostate tumors, suggesting potential utility in the clinical management of the disease by identifying patients at high risk of recurrence who may benefit from adjuvant therapies. Mol Cancer Res; 16(1); 115–23. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0270
      Issue No: Vol. 16, No. 1 (2018)
  • HIF-3{alpha} Promotes Metastatic Phenotypes in Pancreatic Cancer by
           Transcriptional Regulation of the RhoC-ROCK1 Signaling Pathway

    • Authors: Zhou, X; Guo, X, Chen, M, Xie, C, Jiang, J.
      Pages: 124 - 134
      Abstract: Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-2α (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3α (HIF3A) has not been investigated. Therefore, HIF-1α, HIF-2α, and HIF-3α expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3α expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3α expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3α expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1α and HIF-2α expression. HIF-3α protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3α, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3α overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3α promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC–ROCK1 signaling pathway.Implications: HIF3α is overexpressed in pancreatic cancer, and targeting the HIF3α/RhoC–ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis. Mol Cancer Res; 16(1); 124–34. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0256
      Issue No: Vol. 16, No. 1 (2018)
  • Malignant Phenotypes in Metastatic Melanoma are Governed by SR-BI and its
           Association with Glycosylation and STAT5 Activation

    • Authors: Kinslechner, K; Schörghofer, D, Schütz, B, Vallianou, M, Wingelhofer, B, Mikulits, W, Röhrl, C, Hengstschläger, M, Moriggl, R, Stangl, H, Mikula, M.
      Pages: 135 - 146
      Abstract: Metastatic melanoma is hallmarked by elevated glycolytic flux and alterations in cholesterol homeostasis. The contribution of cholesterol transporting receptors for the maintenance of a migratory and invasive phenotype is not well defined. Here, the scavenger receptor class B type I (SCARB1/SR-BI), a high-density lipoprotein (HDL) receptor, was identified as an estimator of melanoma progression in patients. We further aimed to identify the SR-BI–controlled gene expression signature and its related cellular phenotypes. On the basis of whole transcriptome analysis, it was found that SR-BI knockdown, but not functional inhibition of its cholesterol-transporting capacity, perturbed the metastasis-associated epithelial-to-mesenchymal transition (EMT) phenotype. Furthermore, SR-BI knockdown was accompanied by decreased migration and invasion of melanoma cells and reduced xenograft tumor growth. STAT5 is an important mediator of the EMT process and loss of SR-BI resulted in decreased glycosylation, reduced DNA binding, and target gene expression of STAT5. When human metastatic melanoma clinical specimens were analyzed for the abundance of SR-BI and STAT5 protein, a positive correlation was found. Finally, a novel SR-BI–regulated gene profile was determined, which discriminates metastatic from nonmetastatic melanoma specimens indicating that SR-BI drives gene expression contributing to growth at metastatic sites. Overall, these results demonstrate that SR-BI is a highly expressed receptor in human metastatic melanoma and is crucial for the maintenance of the metastatic phenotype.Implications: High SR-BI expression in melanoma is linked with increased cellular glycosylation and hence is essential for a metastasis-specific expression signature. Mol Cancer Res; 16(1); 135–46. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0292
      Issue No: Vol. 16, No. 1 (2018)
  • Functional Genomics Approach Identifies Novel Signaling Regulators of
           TGF{alpha} Ectodomain Shedding

    • Authors: Wilson, J. L; Kefaloyianni, E, Stopfer, L, Harrison, C, Sabbisetti, V. S, Fraenkel, E, Lauffenburger, D. A, Herrlich, A.
      Pages: 147 - 161
      Abstract: Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFB regulatory functions. Inflammatory regulators thus also govern cancer cell growth–promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147–61. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0140
      Issue No: Vol. 16, No. 1 (2018)
  • NF{kappa}B-Mediated Invasiveness in CD133+ Pancreatic TICs Is Regulated by
           Autocrine and Paracrine Activation of IL1 Signaling

    • Authors: Nomura, A; Gupta, V. K, Dauer, P, Sharma, N. S, Dudeja, V, Merchant, N, Saluja, A. K, Banerjee, S.
      Pages: 162 - 172
      Abstract: Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133+ cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-B activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1β (IL1B), which activates an autocrine signaling loop that upregulates NF-B signaling, epithelial–mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1β, the tumor-associated macrophages (TAM) also produced IL1β, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.Implications: This study demonstrates the important role of tumor- and macrophage-derived IL1β stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1β stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs. Mol Cancer Res; 16(1); 162–72. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0221
      Issue No: Vol. 16, No. 1 (2018)
  • Crk Tyrosine Phosphorylation Regulates PDGF-BB-inducible Src Activation
           and Breast Tumorigenicity and Metastasis

    • Authors: Kumar, S; Lu, B, Davra, V, Hornbeck, P, Machida, K, Birge, R. B.
      Pages: 173 - 183
      Abstract: The activity of Src family kinases (Src being the prototypical member) is tightly regulated by differential phosphorylation on Tyr416 (positive) and Tyr527 (negative), a duet that reciprocally regulates kinase activity. The latter negative regulation of Src on Tyr527 is mediated by C-terminal Src kinase (CSK) that phosphorylates Tyr527 and maintains Src in a clamped negative regulated state by promoting an intramolecular association. Here it is demonstrated that the SH2- and SH3-domain containing adaptor protein CrkII, by virtue of its phosphorylation on Tyr239, regulates the Csk/Src signaling axis to control Src activation. Once phosphorylated, the motif (PIpYARVIQ) forms a consensus sequence for the SH2 domain of CSK to form a pTyr239-CSK complex. Functionally, when expressed in Crk–/– MEFs or in Crk+/+ HS683 cells, Crk Y239F delayed PDGF-BB–inducible Src Tyr416 phosphorylation. Moreover, expression of Crk Y239F in HS683 cells delayed Src kinase activation and suppressed the cell-invasive and -transforming phenotypes. Finally, through loss-of-function and epistasis experiments using CRISPR-Cas9–engineered 4T1 murine breast cancer cells, Crk Tyr239 is implicated in breast cancer tumor growth and metastasis in orthotopic immunocompetent 4T1 mice model of breast adenocarcinoma. These findings delineate a novel role for Crk Tyr239 phosphorylation in the regulation of Src kinases, as well as a potential molecular explanation for a long-standing question as to how Crk regulates the activation of Src kinases.Implications: These findings provide new perspectives on the versatility of Crk in cancer by demonstrating how Crk mechanistically drives, through a tyrosine phosphorylation–dependent manner, tumor growth, and metastasis. Mol Cancer Res; 16(1); 173–83. ©2017 AACR.
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0242
      Issue No: Vol. 16, No. 1 (2018)
  • Correction: Inhibition of mTORC1 Kinase Activates Smads 1 and 5 but Not
           Smad8 in Human Prostate Cancer Cells, Mediating Cytostatic Response to

    • Pages: 184 - 184
      PubDate: 2018-01-01T21:05:26-08:00
      DOI: 10.1158/1541-7786.MCR-17-0672
      Issue No: Vol. 16, No. 1 (2018)
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