The Experts below are selected from a list of 13140 Experts worldwide ranked by ideXlab platform
Peijing Zhang - One of the best experts on this subject based on the ideXlab platform.
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zeb1 at the crossroads of epithelial mesenchymal transition metastasis and Therapy Resistance
Cell Cycle, 2015Co-Authors: Peijing ZhangAbstract:Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) in carcinoma cells. EMT not only plays an important role in embryonic development and malignant progression, but is also implicated in cancer Therapy Resistance. It has been hypothesized that carcinoma cells that have undergone EMT acquire cancer stem cell properties including self-renewal, chemoResistance and radioResistance. However, our recent data indicate that ZEB1 regulates radioResistance in breast cancer cells through an EMT-independent mechanism. In this Perspective, we review different mechanisms by which ZEB1 regulates tumor progression and treatment Resistance. Based on studies by us and others, we propose that it is specific EMT inducers like ZEB1, but not the epithelial or mesenchymal state itself, that dictate cancer stem cell properties.
Masato Yano - One of the best experts on this subject based on the ideXlab platform.
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image based detection and targeting of Therapy Resistance in pancreatic adenocarcinoma
Nature, 2016Co-Authors: Nikki K. Lytle, Dawn Jaquish, Frederick D. Park, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp, Marcie KritzikAbstract:The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and Therapy Resistance. Targeting premalignant pancreatic lesions before they progress to pancreatic ductal adenocarcinoma is challenging. Tannishtha Reya and colleagues have found that the stem cell factor encoding for the RNA-binding protein Musashi (Msi) is critical to this progression in genetic mouse models and patient-derived xenografts. They used an image-based approach to follow the cells as they progress to malignancy, and show that the growth of pancreatic tumours can be halted by targeting Msi with antisense oligonucleotides. Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug Resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify Therapy Resistance, and define Msi signalling as a central regulator of pancreatic cancer.
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Image-based detection and targeting of Therapy Resistance in pancreatic adenocarcinoma.
Nature, 2016Co-Authors: Nikki K. Lytle, Dawn Jaquish, Frederick D. Park, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. KoppAbstract:The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and Therapy Resistance.
Marcie Kritzik - One of the best experts on this subject based on the ideXlab platform.
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image based detection and targeting of Therapy Resistance in pancreatic adenocarcinoma
Nature, 2016Co-Authors: Nikki K. Lytle, Dawn Jaquish, Frederick D. Park, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp, Marcie KritzikAbstract:The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and Therapy Resistance. Targeting premalignant pancreatic lesions before they progress to pancreatic ductal adenocarcinoma is challenging. Tannishtha Reya and colleagues have found that the stem cell factor encoding for the RNA-binding protein Musashi (Msi) is critical to this progression in genetic mouse models and patient-derived xenografts. They used an image-based approach to follow the cells as they progress to malignancy, and show that the growth of pancreatic tumours can be halted by targeting Msi with antisense oligonucleotides. Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug Resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify Therapy Resistance, and define Msi signalling as a central regulator of pancreatic cancer.
Nikki K. Lytle - One of the best experts on this subject based on the ideXlab platform.
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Stem cell fate in cancer growth, progression and Therapy Resistance
Nature Reviews Cancer, 2018Co-Authors: Nikki K. Lytle, Alison G. Barber, Tannishtha ReyaAbstract:Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The Therapy Resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, Therapy Resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease.
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image based detection and targeting of Therapy Resistance in pancreatic adenocarcinoma
Nature, 2016Co-Authors: Nikki K. Lytle, Dawn Jaquish, Frederick D. Park, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp, Marcie KritzikAbstract:The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and Therapy Resistance. Targeting premalignant pancreatic lesions before they progress to pancreatic ductal adenocarcinoma is challenging. Tannishtha Reya and colleagues have found that the stem cell factor encoding for the RNA-binding protein Musashi (Msi) is critical to this progression in genetic mouse models and patient-derived xenografts. They used an image-based approach to follow the cells as they progress to malignancy, and show that the growth of pancreatic tumours can be halted by targeting Msi with antisense oligonucleotides. Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug Resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify Therapy Resistance, and define Msi signalling as a central regulator of pancreatic cancer.
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Image-based detection and targeting of Therapy Resistance in pancreatic adenocarcinoma.
Nature, 2016Co-Authors: Nikki K. Lytle, Dawn Jaquish, Frederick D. Park, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. KoppAbstract:The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and Therapy Resistance.
Sandy Widura - One of the best experts on this subject based on the ideXlab platform.
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hypoxia induces phenotypic plasticity and Therapy Resistance in melanoma via the tyrosine kinase receptors ror1 and ror2
Cancer Discovery, 2013Co-Authors: Michael P Oconnell, Meenhard Herlyn, Amanpreet Kaur, Marie R. Webster, Katie Marchbank, Alexander Valiga, Adina Vultur, Ling Li, Jessie Villanueva, Sandy WiduraAbstract:An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for Therapy Resistance. We demonstrate that phenotype switching and subsequent Resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and Therapy Resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate Therapy Resistance.
