Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue
Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment. Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity, whereas single-cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (CXCR4/CD184, CD24, THY1/CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer clinical biopsy specimens from patient-derived xenograft (PDX) models. Th...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Snowden, E., Porter, W., Hahn, F., Ferguson, M., Tong, F., Parker, J. S., Middlebrook, A., Ghanekar, S., Dillmore, W. S., Blaesius, R. Tags: Genomics Source Type: research
14-3-3{sigma} Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2
In this study, we tested the hypothesis that 14-3-3 causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2–M phase following DNA-damaging treatments. We showed that 14-3-3 contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the ot...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chen, Y., Li, Z., Dong, Z., Beebe, J., Yang, K., Fu, L., Zhang, J.-T. Tags: DNA Damage and Repair Source Type: research
EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation
This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma–induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405–17. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Adamik, J., Jin, S., Sun, Q., Zhang, P., Weiss, K. R., Anderson, J. L., Silbermann, R., Roodman, G. D., Galson, D. L. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research
TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma
Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Change...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cabal-Hierro, L., O'Dwyer, P. J. Tags: Cell Death and Survival Source Type: research
A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance
TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulato...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Dimberg, L. Y., Towers, C. G., Behbakht, K., Hotz, T. J., Kim, J., Fosmire, S., Porter, C. C., Tan, A.-C., Thorburn, A., Ford, H. L. Tags: Cell Death and Survival Source Type: research
A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy
This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results i...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: MacDonald, J., Ramos-Valdes, Y., Perampalam, P., Litovchick, L., DiMattia, G. E., Dick, F. A. Tags: Cell Cycle and Senescence Source Type: research
Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis
Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. On the basis of Paget's 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic "seed and soil," but the implications of the primary tumor "soil" have been largely neglected. The rare lethal metastatic "seed" arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and resource reward. Further selection...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: de Groot, A. E., Roy, S., Brown, J. S., Pienta, K. J., Amend, S. R. Tags: Review Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Retraction: Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Tags: Retraction Source Type: research
Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma
This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL. Mol Cancer Res; 15(3); 348–57. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Zhu, F., Hwang, B., Miyamoto, S., Rui, L. Tags: Signal Transduction Source Type: research
Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors
This study reports the novel findings that HER2 increases PARP1 protein via suppression of the let-7a miRNA, which regulates the PARP1 3'-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens. Mol Cancer Res; 15(3); 340–7. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Wielgos, M. E., Rajbhandari, R., Cooper, T. S., Wei, S., Nozell, S., Yang, E. S. Tags: Signal Transduction Source Type: research
Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation
Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently, we reported that mutant, but otherwise functional, p53v172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogues oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP) strongly stabilize and activate p53v172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2. This increase in MDM2 reduced M...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Xie, X., He, G., Siddik, Z. H. Tags: Oncogenes and Tumor Suppressors Source Type: research
Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations
Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers, PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are inv...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Foley, T. M., Payne, S. N., Pasch, C. A., Yueh, A. E., Van De Hey, D. R., Korkos, D. P., Clipson, L., Maher, M. E., Matkowskyj, K. A., Newton, M. A., Deming, D. A. Tags: Oncogenes and Tumor Suppressors Source Type: research
Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC
Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Güttlein, L. N., Benedetti, L. G., Fresno, C., Spallanzani, R. G., Mansilla, S. F., Rotondaro, C., Raffo Iraolagoitia, X. L., Salvatierra, E., Bravo, A. I., Fernandez, E. A., Gottifredi, V., Zwirner, N. W., Llera, A. S., Podhajcer, O. L. Tags: Oncogenes and Tumor Suppressors Source Type: research
LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML
PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo. Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell–like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thu...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Zhou, J., Chan, Z.-L., Bi, C., Lu, X., Chong, P. S. Y., Chooi, J.-Y., Cheong, L.-L., Liu, S.-C., Ching, Y. Q., Zhou, Y., Osato, M., Tan, T. Z., Ng, C. H., Ng, S.-B., Wang, S., Zeng, Q., Chng, W.-J. Tags: Oncogenes and Tumor Suppressors Source Type: research
