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Pancreatic Neoplasms: HELP
Articles by Meredith A. Collins
Based on 10 articles published since 2010
(Why 10 articles?)
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Between 2010 and 2020, Meredith A. Collins wrote the following 10 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Kras as a key oncogene and therapeutic target in pancreatic cancer. 2013

Collins, Meredith A / Pasca di Magliano, Marina. ·Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA. · Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA ; Department of Surgery, University of Michigan Ann Arbor, MI, USA ; Department of Cell and Developmental Biology, University of Michigan Ann Arbor, MI, USA. ·Front Physiol · Pubmed #24478710.

ABSTRACT: Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications.

2 Article Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. 2016

Takano, Shigetsugu / Reichert, Maximilian / Bakir, Basil / Das, Koushik K / Nishida, Takahiro / Miyazaki, Masaru / Heeg, Steffen / Collins, Meredith A / Marchand, Benoît / Hicks, Philip D / Maitra, Anirban / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; II. Medizinische Klinik, Technical University of Munich, Munich 81675, Germany; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; · Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine II, Medical Center, University of Freiburg, 79106 Freiburg, Germany; · Department of Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Translational Molecular Pathology, Sheikh Ahmad bin Zayed Al Nahyan Pancreatic Cancer Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ·Genes Dev · Pubmed #26773005.

ABSTRACT: The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

3 Article Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. 2015

Bednar, Filip / Schofield, Heather K / Collins, Meredith A / Yan, Wei / Zhang, Yaqing / Shyam, Nikhil / Eberle, Jaime A / Almada, Luciana L / Olive, Kenneth P / Bardeesy, Nabeel / Fernandez-Zapico, Martin E / Nakada, Daisuke / Simeone, Diane M / Morrison, Sean J / Pasca di Magliano, Marina. ·Department of Surgery. · Program in Cell and Molecular Biology, Medical Scientist Training Program. · Program in Cell and Molecular Biology. · Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA, Present address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. · Medical Scientist Training Program. · Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. · Department of Surgery, Department of Molecular and Integrative Physiology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. · Children's Research Institute, Department of Pediatrics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and. · Department of Surgery, Program in Cell and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA and marinapa@umich.edu. ·Carcinogenesis · Pubmed #25939753.

ABSTRACT: Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.

4 Article CD44 regulates pancreatic cancer invasion through MT1-MMP. 2015

Jiang, Wei / Zhang, Yaqing / Kane, Kevin T / Collins, Meredith A / Simeone, Diane M / di Magliano, Marina Pasca / Nguyen, Kevin Tri. ·Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. · Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan. · Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan. · Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan. marinapa@umich.edu ktnguyen74@yahoo.com. · Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. marinapa@umich.edu ktnguyen74@yahoo.com. ·Mol Cancer Res · Pubmed #25566991.

ABSTRACT: IMPLICATIONS: This study sets the stage for CD44 and MT1-MMP as therapeutic targets in pancreatic cancer, for which small molecule or biologic inhibitors are available. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/09/10/1541-7786.MCR-14-0076/F1.large.jpg.

5 Article The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling. 2014

Mathew, Esha / Collins, Meredith A / Fernandez-Barrena, Maite G / Holtz, Alexander M / Yan, Wei / Hogan, James O / Tata, Zachary / Allen, Benjamin L / Fernandez-Zapico, Martin E / di Magliano, Marina Pasca. ·From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109. · the Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905. · From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, the Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109. · the Department of Pathology, Michigan Center for Translational Pathology, and. · Departments of Surgery, and. · From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109. · From the Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, the Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109, Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109 Departments of Surgery, and marinapa@umich.edu. ·J Biol Chem · Pubmed #25104358.

ABSTRACT: Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify GLI1, a transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct GLI1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of GLI1 in regulation of the pancreatic microenvironment during this cellular process.

6 Article CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. 2014

Zhang, Yaqing / Yan, Wei / Mathew, Esha / Bednar, Filip / Wan, Shanshan / Collins, Meredith A / Evans, Rebecca A / Welling, Theodore H / Vonderheide, Robert H / di Magliano, Marina Pasca. ·Authors' Affiliations: Departments of Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ·Cancer Immunol Res · Pubmed #24795355.

ABSTRACT: Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer.

7 Article MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. 2014

Collins, Meredith A / Yan, Wei / Sebolt-Leopold, Judith S / Pasca di Magliano, Marina. ·Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, University of Michigan, Ann Arbor, Michigan; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. · Department of Radiology, University of Michigan, Ann Arbor, Michigan. · Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan. Electronic address: marinapa@umich.edu. ·Gastroenterology · Pubmed #24315826.

ABSTRACT: BACKGROUND & AIMS: Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice. METHODS: We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed. RESULTS: PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1. CONCLUSIONS: In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.

8 Article Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. 2013

Zhang, Yaqing / Yan, Wei / Collins, Meredith A / Bednar, Filip / Rakshit, Sabita / Zetter, Bruce R / Stanger, Ben Z / Chung, Ivy / Rhim, Andrew D / di Magliano, Marina Pasca. ·Authors' Affiliations: Departments of Surgery, Pathology, and Cell and Developmental Biology, Department of Internal Medicine-Gastroenterology, Michigan Center for Translational Pathology, Program in Cellular and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Vascular Biology Program, Department of Surgery, Karp Family Research Laboratories, Children's Hospital, Boston, Massachusetts; Gastroenterology Division, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pharmacology, and University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. ·Cancer Res · Pubmed #24097820.

ABSTRACT: Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target.

9 Article Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. 2012

Collins, Meredith A / Brisset, Jean-Christophe / Zhang, Yaqing / Bednar, Filip / Pierre, Josette / Heist, Kevin A / Galbán, Craig J / Galbán, Stefanie / di Magliano, Marina Pasca. ·Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, United States of America. ·PLoS One · Pubmed #23226501.

ABSTRACT: Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer.

10 Article Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. 2012

Collins, Meredith A / Bednar, Filip / Zhang, Yaqing / Brisset, Jean-Christophe / Galbán, Stefanie / Galbán, Craig J / Rakshit, Sabita / Flannagan, Karen S / Adsay, N Volkan / Pasca di Magliano, Marina. ·Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA. ·J Clin Invest · Pubmed #22232209.

ABSTRACT: Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.