A5103162178- Pancreatic and Hepatic Oncology Research
- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Cancer Genomics and Diagnostics
- Phagocytosis and Immune Regulation
- Epigenetics and DNA Methylation
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cancer Research and Treatments
- Cancer Cells and Metastasis
- Immune Cell Function and Interaction
- Chemokine receptors and signaling
- Hedgehog Signaling Pathway Studies
- Colorectal Cancer Treatments and Studies
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- RNA Interference and Gene Delivery
- Single-cell and spatial transcriptomics
- Ferroptosis and cancer prognosis
- Pancreatitis Pathology and Treatment
- Liver Disease Diagnosis and Treatment
- Lung Cancer Treatments and Mutations
- IL-33, ST2, and ILC Pathways
- Nanoparticle-Based Drug Delivery
- Hepatocellular Carcinoma Treatment and Prognosis
- MicroRNA in disease regulation
University of Michigan
2016-2025
VA Ann Arbor Healthcare System
2022-2024
Michigan Medicine
2008-2024
U-M Rogel Cancer Center
2022-2024
Ann Arbor VA Medical Center
2022-2023
Michigan United
2017-2021
Memorial Sloan Kettering Cancer Center
2013-2019
University Health System
2015
National Cancer Institute
2009-2011
National Institutes of Health
2010-2011
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...
Infiltration of tumors with effector T cells is positively associated therapeutic efficacy and patient survival. However, the mechanisms underlying T-cell trafficking to tumor microenvironment remain poorly understood in patients colon cancer. The polycomb repressive complex 2 (PRC2) involved cancer progression, but regulation immunity by epigenetic has yet be investigated. In this study, we examined relationship between PRC2 machinery trafficking. We found that components demethylase...
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 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...
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,...
Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which widely expressed in a range of epithelial malignancies not most tissues. generate high-avidity TCRs employed transgenic mouse model that expresses the human HLA-A*0201 molecule. Mice were immunized two HLA-A*0201-restricted peptides MAGE-A3:...
Recently, the American Joint Committee on Cancer (AJCC) released its 8th edition changes to staging system for hepatocellular cancer (HCC). We sought validate and compare performance 7th using a population-based data set.Using Surveillance, Epidemiology End Results (SEER) database (1998-2013), patients undergoing resection or transplant non-metastatic HCC were identified. Overall survival was estimated Kaplan-Meier method compared log-rank tests. Concordance indices (c-indices) calculated...
Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, identified a unique tumor-specific gene expression signature that includes high C1qa , C1qb Trem2 Chil3 . Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in one marked...
Paramount to the efficacy of immune checkpoint inhibitors is proper selection patients with adequate tumor immunogenicity and a robust but suppressed infiltrate. In colon cancer, immune-based therapies are approved for DNA mismatch repair (MMR) deficiencies, in whom accumulation genetic mutations results increased neoantigen expression, triggering an response that by PD-L1/PD-1 pathway. Here, we report characterization microenvironment MMR-deficient metastatic colorectal cancer using...
Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in United States. Programmed death 1 receptor (PD-1)-programmed ligand (PD-L1) immune checkpoint inhibition been unsuccessful clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell responses various including pancreas. This led us our objective that was develop a clinically relevant vitro organoid model specifically target mechanisms deplete...
Abstract Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, poorly understood. Thus, efforts therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial expressing oncogenic KRAS—a hallmark pancreatic...
The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear with broad range of functions, both in tumor cells and immune within the microenvironment (TME). Activation AhR has been shown to have carcinogenic effect variety organs, through induction cellular proliferation migration, promotion epithelial-to-mesenchymal transition, inhibition apoptosis, among other functions. However, impact on cell function more complicated, pro- anti-tumorigenic roles identified. Although targeting cancer...
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,...