A5070137893- Pancreatic and Hepatic Oncology Research
- Immune cells in cancer
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- Cancer Immunotherapy and Biomarkers
- Cancer Research and Treatments
- Cancer Cells and Metastasis
- Chromatin Remodeling and Cancer
- Cancer Genomics and Diagnostics
- Pancreatic function and diabetes
- Hedgehog Signaling Pathway Studies
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Ferroptosis and cancer prognosis
- Mechanisms of cancer metastasis
- Cancer, Hypoxia, and Metabolism
- Pancreatitis Pathology and Treatment
- Chemokine receptors and signaling
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Immune Cell Function and Interaction
- Single-cell and spatial transcriptomics
- FOXO transcription factor regulation
- Lipoproteins and Cardiovascular Health
University of Michigan
2016-2025
U-M Rogel Cancer Center
2014-2024
Michigan United
2012-2024
Michigan Medicine
2013-2024
Michigan Center for Translational Pathology
2012-2023
Institut de Biologie Moléculaire et Cellulaire
2023
Henry Ford Health System
2023
Ann Arbor VA Medical Center
2010-2023
Henry Ford Hospital
2022
Comprehensive Blood & Cancer Center
2014-2018
Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result a dominant-active form of GTPase. However, how promote pancreatic carcinogenesis not fully understood, and whether oncogenic required for maintenance has been established. To address these questions, we generated two mouse models tumorigenesis: mice transgenic inducible KrasG12D, which allows inducible, pancreas-specific, reversible expression or without inactivation one...
Abstract Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to immunosuppressive microenvironment, we depleted Tregs a model of Contrary our expectations, Treg depletion failed relieve immunosuppression led accelerated tumor progression. We show that key source TGFβ ligands and, accordingly, their reprogramed fibroblast population, with loss tumor-restraining, smooth muscle actin–expressing fibroblasts. Conversely, observed an increase...
Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are predominant population. Distinct subsets have been correlated with tumour promotion and unmasking anti-tumour immunity.The goal study was to determine effect cell depletion on onset progression pancreatic understand relationship between T cell-mediated immunity within microenvironment.Primary mouse were transplanted into CD11b-diphtheria toxin receptor (DTR)...
Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition 18 murine tissues 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals heterogeneity across tumors, identifies coordinated between immune cell subsets in pancreatic ductal adenocarcinoma. Expression CD105 demarks two stable...
Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with presence an oncogenic form Kras. Mice expressing Kras in pancreas recapitulate stepwise progression disease. The inflammatory cytokine interleukin (IL)-6 often expressed by multiple cell types within tumor microenvironment. Here, we show that IL-6 required for maintenance and pancreatic cancer precursor lesions. In fact, lack completely ablates even Mechanistically, synergizes to activate...
Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity incompletely understood. The Hedgehog pathway functions in paracrine manner, with ligands secreted cancer cells signaling to stromal microenvironment. Previous reports investigating role have been contradictory, alternately...
Abstract Cancer metabolism is rewired to support cell survival in response intrinsic and environmental stressors. Identification of strategies target these adaptions an area active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway pancreatic cancer used maintain redox balance. Here, we sought identify metabolic dependencies following GOT1 inhibition exploit this feature provide additional insight into regulation metabolism. Using pharmacological...
Abstract Combinatorial strategies are needed to overcome the resistance of pancreatic cancer immune checkpoint blockade (ICB). DNA damage activates innate response and improves ICB efficacy. Because ATM is an apical kinase in radiation-induced response, we investigated effects inhibition radiation on tumor immunogenicity. was inhibited through pharmacologic genetic human murine models both vitro vivo. Tumor immunogenicity evaluated after alone combination with by assessing TBK1 Type I...
Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of prevalence activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization mesenchymal stem cells (MSC) within human PDA microenvironment, highlighting heterogeneity fibroblast population. Primary patient samples low-passage cancer-associated cultures were found contain unique...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the and key drivers of immunosuppression. TAMs in human murine elevated expression apolipoprotein E (ApoE), mediates cholesterol metabolism has known roles cardiovascular Alzheimer's disease but no role PDAC. We report here...
Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy 1,2 . This mediated in part by complex tumour microenvironment 3 , low vascularity 4 and metabolic aberrations 5,6 Although altered metabolism drives progression, the spectrum of metabolites used as nutrients PDA remains largely unknown. Here we identified uridine fuel for glucose-deprived conditions assessing how more than 175 impacted activity 21 pancreatic cell lines under nutrient...
An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it well appreciated that are immunosuppressive and contribute to the poor response immunotherapy; however, mechanisms immune suppression complex not fully understood. Immunosuppressive classically defined by expression enzyme Arginase 1 (ARG1), which we demonstrated potently expressed tumor-associated from both human patients mouse models. While routinely used as polarization...
Abstract The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from in absence disease and rapid postmortem degradation. We obtained pancreata brain dead donors, thus avoiding any warm ischemia time. 30 donors were diverse age race had no known disease. Histopathologic analysis samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions most individuals irrespective age. Using a combination multiplex IHC, single-cell RNA sequencing,...
Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels how cope with such nutrition is critical understand metabolism underpinning cell biology. Previously, we performed quantitative metabolomics interstitial fluid (the local perfusate) murine pancreatic ductal adenocarcinoma (PDAC) tumors comprehensively characterize availability these tumors. Here, develop
Lung cancer is the leading cause of deaths in United States. New targeted therapies against once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to inhibitors almost inevitably occurs; can be driven by tumor cell-intrinsic changes or microenvironment. Here, we utilized a genetically engineered mouse model KRASG12D-driven lung that allows for inducible and reversible expression oncogene: activation KRASG12D induces growth; conversely,...