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Trakala M.,Cell Division and Cancer Group | Fernandez-Miranda G.,Cell Division and Cancer Group | De Castro I.P.,Cell Division and Cancer Group | Heeschen C.,Stem Cells and Cancer Group | Malumbres M.,Cell Division and Cancer Group
Cell Cycle | Year: 2013

Aurora kinase B is a critical component of the chromosomal passenger complex, which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. By using conditional knockout cells and chemical inhibition, we show here that inactivation of Aurora B results in delayed G 1/S transition and premature mitotic exit. Aurora B deficiency results in delayed DNA replication in cultured fibroblasts as well as liver cells after hepatectomy. This is accompanied by increased transcription of the cell cycle inhibitor p21Cip1. Lack of Aurora B does not prevent mitotic entry but results in a premature exit from prometaphase in the presence of increased p21Cip1-Cdk1 inactive complexes. Aurora B-null cells display reduced degradation of cyclin B1, suggesting the presence of phenomenon known as adaptation to the mitotic checkpoint, previously described in yeast. Elimination of p21Cip1 rescues Cdk1 activity and prevents premature mitotic exit in Aurora B-deficient cells. These results suggest that Aurora B represses p21Cip1, preventing delayed DNA replication, Cdk inhibition and premature mitotic exit. The upregulation of p21Cip1 observed after inhibitio of Aurora B may haves important implications in cell cycle progression, tetraploidy, senescence or cancer therapy. Copyright © 2013 Landes Bioscience. Source


Cioffi M.,Stem Cells and Cancer Group | Heeschen C.,Stem Cells and Cancer Group
OncoImmunology | Year: 2012

Pancreatic cancer is a highly aggressive and deadly disease harboring a distinct population of cancer stem cells (CSC) that is not affected by conventional therapies. A new therapeutic approach using the EpCAM/CD3-bispecific antibody MT110 is capable of activating and redirecting cytotoxic T cells to eliminate primary human pancreatic cancer stem cells, which resulted in long-term survival of preclinical xenografts models. © 2012 Landes Bioscience. Source


Sainz B.,Stem Cells and Cancer Group | Sainz B.,Autonomous University of Madrid | Martin B.,Autonomous University of Madrid | Tatari M.,Stem Cells and Cancer Group | And 3 more authors.
Cancer Research | Year: 2014

Cancer stem cells (CSC) are thought to play a major role in the development and metastatic progression of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Likewise, the tumor microenvironment contributes critical support in this setting, including from tumor stromal cells and tumor-associated macrophages (TAM) that contribute structural and paracrine-mediated supports, respectively. Here, we show that TAMs secrete the IFN-stimulated factor ISG15, which enhances CSC phenotypes in PDAC in vitro and in vivo. ISG15 was preferentially and highly expressed by TAM present in primary PDAC tumors resected from patients. ISG15 was secreted by macrophages in response to secretion of IFNb by CSC, thereby reinforcing CSC selfrenewal, invasive capacity, and tumorigenic potential. Overall, our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression. ©2014 AACR. Source


Cioffi M.,Stem Cells and Cancer Group | Trabulo S.M.,Stem Cells and Cancer Group | Sanchez-Ripoll Y.,Stem Cells and Cancer Group | Miranda-Lorenzo I.,Stem Cells and Cancer Group | And 10 more authors.
Gut | Year: 2015

Objective Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. Design Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. Results We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. Conclusions Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs. Source


Cioffi M.,Stem Cells and Cancer Group | Trabulo S.,Stem Cells and Cancer Group | Trabulo S.,Barts Cancer Institute | Hidalgo M.,Gastrointestinal Cancer Clinical Research Unit | And 8 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-Associated macrophages (TAM). The presence of TAMs is associated with poor clinical outcome, and their overall role, therefore, appears to be protumorigenic. The don't eat me signal CD47 on cancer cells communicates to the signal regulatory protein-A on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells, including cancer stem cells (CSC), as the exclusively tumorigenic population. Experimental Design: We studied in vitro and in vivo the effects ofCD47inhibition on CSCs using a large set of primary pancreatic cancer (stem) cells as well as xenografts of primary human PDAC tissue. Results: CD47 was highly expressed on CSCs, but not on other nonmalignant cells in the pancreas. Targeting CD47 efficiently enhanced phagocytosis of a representative set of primary human pancreatic cancer (stem) cells and, even more intriguingly, also directly induced their apoptosis in the absence of macrophages during long-Term inhibition of CD47. In patient-derived xenograft models, CD47 targeting alone did not result in relevant slowing of tumor growth, but the addition of gemcitabine or Abraxane resulted in sustained tumor regression and prevention of disease relapse long after discontinuation of treatment. Conclusions: These data are consistent with efficient in vivo targeting of CSCs, and strongly suggest that CD47 inhibition could be a novel adjuvant treatment strategy for PDAC independent of underlying and highly variable driver mutations. © 2015 American Association for Cancer Research. Source

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