Abstract A22: Preclinical evaluation of Bmi1 inhibition in pancreatic ductal adenocarcinoma
Pancreatic Ductal Adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of 6% and a rising mortality rate. The majority of patients present with advanced disease that is unresponsive to chemotherapy, highlighting the need for novel therapeutic strategies. Bmi1, a member of the Polycomb Group (PcG) family of transcriptional repressors, is known to be upregulated in PDA beginning in early pre-malignancy. Elevated Bmi1 expression in pancreatic tumors has been shown to correlate with poor prognosis, increased metastasis, and chemotherapy resistance in pati...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Eberle, J. A., Yuan, H., Palermo, C., Sastra, S. A., Cao, L., Moon, Y.-c., Dumble, M., Davis, T., Olive, K. P. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA21: Mitogenic signaling and the RB/p53 network
Cells entering the division cycle from a quiescent state (G0) in response to mitogenic cues synthesize one or more D-type cyclins (D1, D2, D3) that assemble in G1 phase with cyclin-dependent kinases CDK4 and/or CDK6. Notably, the transcription, assembly with CDK 4/6, and stability of D-type cyclins are each mitogen-dependent steps. Accumulation of cyclin D-dependent kinases in G1 phase leads to the progressive phosphorylation of the retinoblastoma protein (RB), facilitating transcription of E2F-responsive genes, including cyclins E and A, whose CDK2-dependent functions are normally required in S phase. Moreover, the stoich...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sherr, C. J. Tags: Keynote Address: Oral Presentations - Invited Abstracts Source Type: research
Abstract A21: Epigenetic regulation of cell cycle progression at the G2/M transition and mitosis in high-risk leukemia
In conclusion, our results reveal that: 1) Ikaros functions as a tumor suppressor by repressing transcription of genes that are critical for G/M transition (CDC2) and mitotic progression (ANAPC1 and ANAPC7); 2) Ikaros represses transcription by inducing two distinct epigenetic alterations at promoters of its target genes and 3) CK2 inhibition with CX-4945 restores Ikaros function as a transcriptional regulator of CDC2, ANAPC1 and ANAPC7 in high-risk leukemia. These results provide novel insights into the control of cell cycle progression in high-risk leukemia and the mechanisms by which CK2 inhibitors exert their therapeut...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Song, C., Gowda, C., Ding, Y., Payne, K. J., Dovat, S. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA20: Exploiting CDK2-driven replication stress to repurpose cancer chemotherapy
Cyclin-dependent kinase 2 (CDK2) coordinates diverse process, including cell cycle entry and progression, DNA replication, and DNA damage and replication stress responses. Cancers frequently contain mutations in genes that regulate CDK2, which is also activated by oncogenic signaling. Because cancers have abnormally high CDK2 activity, most therapeutic strategies seek to inhibit CDK2. Our studies of CDK2 function during replication stress suggest an alternate approach: to harness high CDK2 activity as a therapeutic modality to cause irreparable DNA damage. In order to study the functions of CDK2 inhibitory phosphorylation ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Richards, H., Zhao, H., Hughes, B. T., Clurman, B. E. Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research
Abstract A20: Excess centrosomes induce p53-dependent senescence in endothelial cells
Excess centrosomes (>2 centrosomes/cell), which are prevalent in both tumor cells and tumor endothelial cells, lead to aneuploidy and chromosome instability. Therefore, understanding how excess centrosomes affect cell behaviors is critical for studying tumor progression and tumor angiogenesis. As demonstrated by previous literature, cells with excess centrosomes routinely undergo bipolar cell division to produce viable progeny. However, we found that endothelial cells were not able to maintain the percentage of cells with excess centrosomes, suggesting that excess centrosomes had a negative impact on endothelial cell cy...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yu, Z., Kushner, E., Bautch, V. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA19: Mechanisms of alternative telomere recombination
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, approximately 10-15% employ a recombination-dependent telomere maintenance pathway known as Alternative Lengthening of Telomeres (ALT), an incompletely understood process that is characterized by multi-telomere clusters. We have recently shown that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis (Cho et. al. Cell 2014). Damaged tel...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Greenberg, R. A. Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research
Abstract B19: The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma
A prominent mechanism through which tumors develop resistance to DNA damaging chemotherapeutic agents is by cancer cells preferentially arresting in S-phase, thereby acquiring the ability to repair drug-induced DNA damage and consequently evading apoptosis. Combining DNA damaging therapies with targeted approaches that disrupt the DNA damage repair process may therefore prove to be more effective against such tumors. The developmentally important transcription factor TBX2 has been suggested as a novel anti-cancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferati...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kimani, S., Wansbelen, S., Davis, E., Peres, J., Prince, S. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A18: G1 cell cycle arrest is required for invasive behavior
The ability for a cell to breach the surrounding basement membrane and adopt an invasive phenotype is a critical, but poorly understood step in the progression of cancer. Like many aspects of cancer cell behavior, the genetic programs that regulate invasive behavior are likely shared with normal cell biological processes, as invasion occurs during embryonic development and immune surveillance. Due to difficulties of studying this dynamic behavior in vivo, elucidating the genetic and epigenetic controls of cell invasive activity has been difficult. Our laboratory uses a unique in vivo model to examine cell invasion that com...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kohrman, A. Q., Chandhok, M., Zhang, W., Matus, D. Q. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B17: Targeting MK2 to improve temozolomide efficacy in glioblastoma
Glioblastoma is the most prevalent and aggressive form of brain cancer. The heterogeneous nature and survival mechanisms that glioblastoma tumors develop impede chemotherapy efficacy of temozolomide (TMZ) and result in tumor relapse. The p38 MAPK and its downstream kinase MK2 have been well established in regulating signaling pathways influencing inflammation, cell division and differentiation, as well as cell motility in response to a wide range of extracellular stimuli. Recent studies have identified p38 MAPK-MK2 pathway as an effector kinase complex that is activated following DNA damage and results in cell cycle arrest...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Gurgis, F., Day, B., Stringer, B., Johns, T. G., Munoz, L. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A17: Cell cycle control through DREAM and MMB complexes
The loss of cell cycle control is the most recognized trait of cancer cells. The ability of cells to exit the cell cycle has recently been shown to be dependent upon a large multi-protein repressor complex called DREAM. This complex represses the expression of all cell cycle genes during reversible cell cycle exit. In cycling cells, DREAM is disassembled and some of DREAM associated proteins form a new complex to promote cell cycle gene expression. These proteins that can act together both as repressors and activators of cell cycle gene expression are called the MuvB core. The MuvB core interacts with B-Myb during S phase ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Guiley, K., Rubin, S. M. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA16: Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer
E2F transcriptional activators and repressors regulate cell cycle-dependent gene expression. Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output we show that mouse development is relatively insensitive to alterations in E2F levels and composition. However, modest increases in E2F output resulted in spontaneous hepatocellular carcinoma (HCC) without additional organ involvement, whereas decreases protected against HCC. Cell type- and temporal-specific gene ablation strategies defined a cell-autonomous oncogenic role for E2F1/3B and a tumor suppressor role for E2F7/8 in hepatocytes. Geneti...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Leone, G. W. Tags: E2F Family Functions: Alterations and Consequences: Oral Presentations - Invited Abstracts Source Type: research
Abstract B16: The nuclear IGF-1R regulates DNA damage tolerance through tyrosine phosphorylation of PCNA in human embryonic stem cells
Conclusions: Our results demonstrate a novel role of nIGF-1R in regulating the DNA damage tolerance pathway through PCNA phosphorylation and ubiquitination, potentially maintaining genomic stability in in hESC and in normal fibroblasts. In contrast, nIGF-1R does not interact with PCNA in cancer cell lines.Citation Format: Ahmed Waraky, Yingbo Lin, Eiman Aleem, Olle Larsson. The nuclear IGF-1R regulates DNA damage tolerance through tyrosine phosphorylation of PCNA in human embryonic stem cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Waraky, A., Lin, Y., Aleem, E., Larsson, O. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA15: The consequences of pRb inactivation: insights from a proteomic analysis of Rb loss
The retinoblastoma tumor suppressor protein associates with chromatin and regulates gene expression. The transcriptional signatures associated with RB1/Rb mutation are thought to give a picture of the cellular changes that occur when pRB is lost. We used proteomic profiling to examine the changes caused by the ablation of Rb in mouse lung and colon tissues, and compared these with transcript profiles. While the transcription of classic E2F target genes increased similarly in Rbko lung and colon, effects on protein levels were context-dependent. Proteomic changes were identified that were similar between Rb-mutant tissues b...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nicolay, B. N., Danielian, P. S., Kottakis, F., Lapek, J. D., Sanidas, I., Miles, W. O., Dehnad, M., Tschöp, K., Gierut, J. J., Manning, A. L., Morris, R., Haigis, K., Bardeesy, N., Lees, J. A., Haas, W., Dyson, N. J. Tags: E2F Family Functions: Alterations and Consequences: Oral Presentations - Invited Abstracts Source Type: research
Abstract B15: Synergistic functions of E2F7 and E2F8 are critical to suppress stress induced skin cancer
E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Westendorp, B., Thurlings, I., Martinez-Lopez, L., Zijp, M., Kuiper, R., Tooten, P., Vos, H., Burgering, B., Bruin, A. d. Tags: E2F Family Functions: Alterations and Consequences: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A15: Sin3B: a non-classical tumor suppressor
Perturbations in cell cycle regulators elicit hyperproliferation and the inability of cells to exit the cell cycle, which are common occurrences in cancer. Recently, we have demonstrated that Sin3B, an essential component of the mammalian histone deacetylase repressor complex, is required for oncogene-induced senescence both in vitro and in vivo. Surprisingly, primary Sin3B-null cells are not readily transformed upon ectopic expression of oncogenic Ras. Thus, these observations indicate that loss of Sin3B uncouples the ability to undergo senescence from the sensitivity to transformation in primary cells. To better understa...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Bainor, A. J., Ueberheide, B., David, G. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research
