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Pancreatic Neoplasms: HELP
Articles by Michael C. Schmid
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, Michael C. Schmid wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Impact of tumour associated macrophages in pancreatic cancer. 2013

Mielgo, Ainhoa / Schmid, Michael C. ·Liverpool Cancer Research UK Centre, Liverpool L7 8XP, UK. ·BMB Rep · Pubmed #23527856.

ABSTRACT: During cancer progression, bone marrow derived myeloid cells, including immature myeloid cells and macrophages, progressively accumulate at the primary tumour site where they contribute to the establishment of a tumour promoting microenvironment. A marked infiltration of macrophages into the stromal compartment and the generation of a desmoplastic stromal reaction is a particular characteristic of pancreatic ductal adenocarcinoma (PDA) and is thought to play a key role in disease progression and its response to therapy. Tumour associated macrophages (TAMs) foster PDA tumour progression by promoting angiogenesis, metastasis, and by suppressing an anti-tumourigenic immune response. Recent work also suggests that TAMs contribute to resistance to chemotherapy and to the emergence of cancer stem-like cells. Here we will review the current understanding of the biology and the pro-tumourigenic functions of TAMs in cancer and specifically in PDA, and highlight potential therapeutic strategies to target TAMs and to improve current therapies for pancreatic cancer.

2 Article Blockade of Stromal Gas6 Alters Cancer Cell Plasticity, Activates NK Cells, and Inhibits Pancreatic Cancer Metastasis. 2020

Ireland, Lucy / Luckett, Teifion / Schmid, Michael C / Mielgo, Ainhoa. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. ·Front Immunol · Pubmed #32174917.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts, and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis, and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy.

3 Article MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages. 2019

Babicky, Michele L / Harper, Megan M / Chakedis, Jeffery / Cazes, Alex / Mose, Evangeline S / Jaquish, Dawn V / French, Randall P / Childers, Betzaira / Alakus, Hakan / Schmid, Michael C / Foubert, Phillippe / Miyamoto, Jaclyn / Holman, Patrick J / Walterscheid, Zakkary J / Tang, Chih-Min / Varki, Nissi / Sicklick, Jason K / Messer, Karen / Varner, Judith A / Waltz, Susan E / Lowy, Andrew M. ·Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA, 92093, USA. · Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA. · Department of Family Medicine and Epidemiology, University of California, San Diego, La Jolla, CA, 92093, USA. · Department of Cancer Biology, University of Cincinnati College of Medicine, and Research Service, Cincinnati Veteran's Administration Medical Center, Cincinnati, OH, 45267, USA. · Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA, 92093, USA. alowy@ucsd.edu. ·Oncogene · Pubmed #30967626.

ABSTRACT: The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.

4 Article Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer. 2018

Quaranta, Valeria / Rainer, Carolyn / Nielsen, Sebastian R / Raymant, Meirion L / Ahmed, Muhammad S / Engle, Dannielle D / Taylor, Arthur / Murray, Trish / Campbell, Fiona / Palmer, Daniel H / Tuveson, David A / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. mschmid@liverpool.ac.uk. ·Cancer Res · Pubmed #29789416.

ABSTRACT: The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8

5 Article Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. 2016

Ireland, Lucy / Santos, Almudena / Ahmed, Muhammad S / Rainer, Carolyn / Nielsen, Sebastian R / Quaranta, Valeria / Weyer-Czernilofsky, Ulrike / Engle, Danielle D / Perez-Mancera, Pedro A / Coupland, Sarah E / Taktak, Azzam / Bogenrieder, Thomas / Tuveson, David A / Campbell, Fiona / Schmid, Michael C / Mielgo, Ainhoa. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Medicine and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. · Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. ·Cancer Res · Pubmed #27742686.

ABSTRACT: Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163

6 Article Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression. 2016

Kaneda, Megan M / Cappello, Paola / Nguyen, Abraham V / Ralainirina, Natacha / Hardamon, Chanae R / Foubert, Philippe / Schmid, Michael C / Sun, Ping / Mose, Evangeline / Bouvet, Michael / Lowy, Andrew M / Valasek, Mark A / Sasik, Roman / Novelli, Francesco / Hirsch, Emilio / Varner, Judith A. ·Moores Cancer Center, University of California, San Diego, La Jolla, California. · Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, Mudanjiang Medical University, Mudanjiang, China. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Surgery, University of California, San Diego, La Jolla, California. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. · Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California. · Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. · Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Molecular Biotechnology Center, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. ·Cancer Discov · Pubmed #27179037.

ABSTRACT: SIGNIFICANCE: We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870-85. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

7 Article Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. 2016

Nielsen, Sebastian R / Quaranta, Valeria / Linford, Andrea / Emeagi, Perpetua / Rainer, Carolyn / Santos, Almudena / Ireland, Lucy / Sakai, Takao / Sakai, Keiko / Kim, Yong-Sam / Engle, Dannielle / Campbell, Fiona / Palmer, Daniel / Ko, Jeong Heon / Tuveson, David A / Hirsch, Emilio / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea. · Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy. ·Nat Cell Biol · Pubmed #27088855.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

8 Article UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis. 2016

Abu-Alainin, Wafa / Gana, Thompson / Liloglou, Triantafillos / Olayanju, Adedamola / Barrera, Lawrence N / Ferguson, Robert / Campbell, Fiona / Andrews, Timothy / Goldring, Christopher / Kitteringham, Neil / Park, Brian K / Nedjadi, Taoufik / Schmid, Michael C / Slupsky, Joseph R / Greenhalf, William / Neoptolemos, John P / Costello, Eithne. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · Department of Pharmacology and Therapeutics, University of Liverpool, UK. · Department of Pathology, Royal Liverpool University Hospital, UK. ·J Pathol · Pubmed #26497117.

ABSTRACT: The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1-mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2-regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K-Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2-mediated cellular protection. Since UHRF1 over-expression occurs in other cancers, its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers.