8 results on '"Samuel E.J. Preston"'
Search Results
2. Supplementary Figure from Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype
- Author
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Wilson H. Miller, Jonathan D. Licht, Sonia V. del Rincón, Koren K. Mann, Nathalie A. Johnson, Ryan N. Rys, Mena Kinal, Alberto Riva, Madelyn Jean Abraham, Daphné Dupéré-Richer, Filippa Pettersson, Audrey Emond, and Samuel E.J. Preston
- Abstract
Supplementary Figure from Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype
- Published
- 2023
3. Data from Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype
- Author
-
Wilson H. Miller, Jonathan D. Licht, Sonia V. del Rincón, Koren K. Mann, Nathalie A. Johnson, Ryan N. Rys, Mena Kinal, Alberto Riva, Madelyn Jean Abraham, Daphné Dupéré-Richer, Filippa Pettersson, Audrey Emond, and Samuel E.J. Preston
- Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for 40% of non-Hodgkin lymphoma, and 30% to 40% of patients will succumb to relapsed/refractory disease (rrDLBCL). Patients with rrDLBCL generally have low long-term survival rates due to a lack of efficient salvage therapies. Small-molecule inhibitors targeting the histone methyltransferase EZH2 represent an emerging group of novel therapeutics that show promising clinical efficacy in patients with rrDLBCL. The mechanisms that control acquired resistance to this class of targeted therapies, however, remain poorly understood. Here, we develop a model of resistance to the EZH2 inhibitor (EZH2i) GSK343 and use RNA-seq data and in vitro investigation to show that GCB (germinal center B-cell)-DLBCL cell lines with acquired drug resistance differentiate toward an ABC (activated B-cell)-DLBCL phenotype. We further observe that the development of resistance to GSK343 is sufficient to induce cross-resistance to other EZH2i. Notably, we identify the immune receptor SLAMF7 as upregulated in EZH2i-resistant cells, using chromatin immunoprecipitation profiling to uncover the changes in chromatin landscape remodeling that permit this altered gene expression. Collectively, our data reveal a previously unreported response to the development of EZH2i resistance in DLBCL, while providing strong rationale for pursuing investigation of dual-targeting of EZH2 and SLAMF7 in rrDLBCL.
- Published
- 2023
4. Supplementary Data from MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ
- Author
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Wilson H. Miller, Sonia V. del Rincón, Lynne-Marie Postovit, Muriel Brackstone, Nadia V. Giannakopoulos, Moulay Alaoui-Jamali, Luke McCaffrey, Fariba Behbod, Michael Witcher, Frédéric Amant, Krikor Bijian, Sara Al Habyan, Maud Marques, Jose Torres, Jie Su, Dany Plourde, Yao Zhan, Christophe Gonçalves, Mark Basik, Guihua Zhang, Henry Yu, Hanne Lefrère, Zahra Talat, Samuel E.J. Preston, William Yang, Fan Huang, Jessica N. Nichol, Vivian Z. Li, and Qianyu Guo
- Abstract
The supplementary material file provides extended data to further support that the MNK1/NODAL pathway plays a critical role in the DCIS to IDC transition, as well as information about the antibodies and statistical analyses used in this study.
- Published
- 2023
5. Data from MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ
- Author
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Wilson H. Miller, Sonia V. del Rincón, Lynne-Marie Postovit, Muriel Brackstone, Nadia V. Giannakopoulos, Moulay Alaoui-Jamali, Luke McCaffrey, Fariba Behbod, Michael Witcher, Frédéric Amant, Krikor Bijian, Sara Al Habyan, Maud Marques, Jose Torres, Jie Su, Dany Plourde, Yao Zhan, Christophe Gonçalves, Mark Basik, Guihua Zhang, Henry Yu, Hanne Lefrère, Zahra Talat, Samuel E.J. Preston, William Yang, Fan Huang, Jessica N. Nichol, Vivian Z. Li, and Qianyu Guo
- Abstract
The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A–derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease.Significance:These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.
- Published
- 2023
6. Phosphorylation of eIF4E in the stroma drives the production and spatial organisation of collagen type I in the mammary gland
- Author
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Samuel E.J. Preston, Margarita Bartish, Vincent R. Richard, Arash Aghigh, Christophe Gonçalves, Julian Smith-Voudouris, Fan Huang, Paméla Thébault, Aurélie Cleret-Buhot, Réjean Lapointe, François Légaré, Lynne-Marie Postovit, René P. Zahedi, Christoph H. Borchers, Wilson H. Miller Jr., and Sonia V. del Rincón
- Subjects
Proteomics ,Breast Neoplasms ,Collagen Type I ,Mice ,Eukaryotic Initiation Factor-4E ,Serine ,Tumor Microenvironment ,Animals ,Humans ,Female ,Collagen ,Phosphorylation ,Mammary Glands, Human ,Molecular Biology - Abstract
The extracellular matrix (ECM) plays critical roles in breast cancer development. Whether ECM composition is regulated by the phosphorylation of eIF4E on serine 209, an event required for tumorigenesis, has not been explored. Herein, we used proteomics and mouse modeling to investigate the impact of mutating serine 209 to alanine on eIF4E (i.e., S209A) on mammary gland (MG) ECM. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD028953. We discovered that S209A knock-in mice, expressing a non-phosphorylatable form of eIF4E, have less collagen-I deposition in native and tumor-bearing MGs, leading to altered tumor cell invasion. Additionally, phospho-eIF4E deficiency impacts collagen topology; fibers at the tumor-stroma boundary in phospho-eIF4E-deficient mice run parallel to the tumor edge but radiate outwards in wild-type mice. Finally, a phospho-eIF4E-deficient tumor microenvironment resists anti-PD-1 therapy-induced collagen deposition, correlating with an increased anti-tumor response to immunotherapy. Clinically, we showed that collagen-I and phospho-eIF4E are positively correlated in human breast cancer samples, and that stromal phospho-eIF4E expression is influenced by tumor proximity. Together, our work defines the importance of phosphorylation of eIF4E on S209 as a regulator of MG collagen architecture in the tumor microenvironment, thereby positioning phospho-eIF4E as a therapeutic target to augment response to therapy.
- Published
- 2021
7. Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype
- Author
-
Samuel E.J. Preston, Audrey Emond, Filippa Pettersson, Daphné Dupéré-Richer, Madelyn Jean Abraham, Alberto Riva, Mena Kinal, Ryan N. Rys, Nathalie A. Johnson, Koren K. Mann, Sonia V. del Rincón, Jonathan D. Licht, and Wilson H. Miller
- Subjects
Cancer Research ,Indazoles ,Phenotype ,Oncology ,Drug Resistance, Neoplasm ,Pyridones ,Cell Line, Tumor ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Lymphoma, Large B-Cell, Diffuse ,Article - Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for 40% of non-Hodgkin lymphoma, and 30% to 40% of patients will succumb to relapsed/refractory disease (rrDLBCL). Patients with rrDLBCL generally have low long-term survival rates due to a lack of efficient salvage therapies. Small-molecule inhibitors targeting the histone methyltransferase EZH2 represent an emerging group of novel therapeutics that show promising clinical efficacy in patients with rrDLBCL. The mechanisms that control acquired resistance to this class of targeted therapies, however, remain poorly understood. Here, we develop a model of resistance to the EZH2 inhibitor (EZH2i) GSK343 and use RNA-seq data and in vitro investigation to show that GCB (germinal center B-cell)-DLBCL cell lines with acquired drug resistance differentiate toward an ABC (activated B-cell)-DLBCL phenotype. We further observe that the development of resistance to GSK343 is sufficient to induce cross-resistance to other EZH2i. Notably, we identify the immune receptor SLAMF7 as upregulated in EZH2i-resistant cells, using chromatin immunoprecipitation profiling to uncover the changes in chromatin landscape remodeling that permit this altered gene expression. Collectively, our data reveal a previously unreported response to the development of EZH2i resistance in DLBCL, while providing strong rationale for pursuing investigation of dual-targeting of EZH2 and SLAMF7 in rrDLBCL.
- Published
- 2021
8. MNK2 governs the macrophage antiinflammatory phenotype
- Author
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Anne Laure Joly, Christina Seitz, Samuel E.J. Preston, Majken Wallerius, Talin Ebrahimian, Stephanie Lehoux, Sonia V. del Rincón, Jonas Bergh, Ola Larsson, Johannes Ristau, Kristian Pietras, Laia Masvidal, Yangxun Pan, John Andersson, Mario Leonardo Squadrito, Christophe Goncalves, Luigi Naldini, Tatjana Wallmann, Hui Liu, Thomas Kerzel, Margarita Bartish, Sabrina de Souza Ferreira, Dongmei Tong, Charlotte Rolny, Vincent van Hoef, Bartish, M., Tong, D., Pan, Y., Wallerius, M., Liu, H., Ristau, J., de Souza Ferreira, S., Wallmann, T., van Hoef, V., Masvidal, L., Kerzel, T., Joly, A. -L., Goncalves, C., Preston, S. E. J., Ebrahimian, T., Seitz, C., Bergh, J., Pietras, K., Lehoux, S., Naldini, L., Andersson, J., Squadrito, M. L., del Rincon, S. V., Larsson, O., and Rolny, C.
- Subjects
Primary Cell Culture ,MNK2 ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Proinflammatory cytokine ,Mice ,Cell Plasticity ,Neoplasms ,Gene expression ,EIF4E ,Macrophage ,Animals ,Humans ,Naphthyridines ,Phosphorylation ,PI3K/AKT/mTOR pathway ,Multidisciplinary ,Chemistry ,Kinase ,T cell activation ,Macrophages ,TOR Serine-Threonine Kinases ,Tumor-associated macrophages ,MRNA translation ,Biological Sciences ,Coculture Techniques ,Cell biology ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Eukaryotic Initiation Factor-4E ,Gene Knockdown Techniques ,MCF-7 Cells ,Female ,Tumor Escape ,Signal Transduction - Abstract
Tumor-associated macrophages (TAMs) continuously fine tune their immune modulatory properties, but how gene expression programs coordinate this immune cell plasticity is largely unknown. Selective mRNA translation, controlled by MNK1/MNK2 and mTOR pathways impinging on eIF4E, facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs. Using polysome profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies. These alterations in gene expression paralleled accumulation of antiinflammatory macrophages with augmented phosphorylation of eIF4E, a target of the MNK1 and MNK2 kinases, known to selectively modulate mRNA translation. Furthermore, suppression of the MNK2, but not the mTOR signaling pathway, reprogrammed antiinflammatory macrophages toward a proinflammatory phenotype with the ability to activate CD8(+) T cells. Thus, selective changes of mRNA translation depending on MNK2 signaling represents a key node regulating macrophage antiinflammatory functions.
- Published
- 2020
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