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Principal Investigator: Benjamin Leland Woolbright
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $162,000
Funding agency: National Cancer Institute
ABSTRACT
Bladder cancer (BCa) is predominantly a disease of aging with the risk of developing invasive disease peaking
in the 8th decade of life. Elderly patients have higher rates of co-morbidities and are thus often not suitable
candidates for standard of care surgery and/or chemotherapy or immunotherapy. Moreover, unlike other cancers
such as breast and colon, BCa in the elderly is more aggressive and associated with poorer outcomes. Aging is
also associated with both increased baseline levels of tissue inflammation and major differences in the gut
microbiome. Aging-associated changes in the microbiome and inflammation have been linked to cancer
incidence and progression, and poorer outcomes with immunotherapy and chemotherapy in multiple cancers. In
spite of the numerous studies describing these changes, mechanistic studies attempting to understand how
these changes impact BCa are comparatively absent. To investigate this phenomenon in a translational setting,
we exposed young (8 weeks at start) and older mice (78 weeks at start) to the model BCa carcinogen N-Butyl-
N-(4-hydroxybutyl) nitrosamine (BBN). We found older animals had increased baseline levels of inflammation
and developed larger, more aggressive tumors after 16 weeks of BBN. Older animals also had more inflamed
tumors as we found higher levels of recruited neutrophils and macrophages. Innate immune cells, particularly
neutrophils, have been associated with a pro-tumorigenic phenotype in colon, liver, and other cancers and thus
we proposed altered inflammation may be a cause of the larger tumors. As aging results in major changes in
microbial diversity, we also evaluated 16S sequencing of the fecal microbiome to determine if these animals
underwent similar changes. While the microbiomes were similar at the start of the study, we found major
divergences between the groups over time, with significant differences in ß-diversity between young or old
animals with cancer. This has led to the hypothesis that gut dysfunction drives neutrophil recruitment to enhance
BCa formation in aged animals. In Specific Aim 1, I will assess gut dysfunction and microbial divergence over
time in young and old animals. In Specific Aim 2, I will use fecal microbiota transplantation to determine if
switching microbiota constituency between young and old animals during tumor formation can affect BCa
tumorigenesis. In Specific Aim 3, I will use pharmacological and genetic inhibition of specific aspects of neutrophil
biology to evaluate the role of neutrophils in BCa development in young and old mice. Completion of these aims
will provide the first murine model for aging related increases in BCa. Moreover, this research sets the stage for
future R01 studies aimed at detailed mechanistic studies understanding the signaling mechanisms that mediate
these observations as well as studies using combination therapy with immunotherapy as a novel treatment for
BCa. Dedicated time to perform these studies will serve as the critical preliminary data to propel the applicant,
Dr. Ben Woolbright, towards an independent career.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><5-Isothiocyanatofluorescein><Abscission><Active Oxygen><Affect><Aging><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Assay><Back><Bioassay><Biological Assay><Biology><Bladder><Bladder Cancer><Bladder Urinary System><Blood><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood monocyte><Body Tissues><Breast><CD8><CD8B><CD8B1><CD8B1 gene><CDw128b Antigens><CXC Chemokine Receptor 2><CXCR2 Protein><CXCR2 Receptors><Cancer Causing Agents><Cancer Model><CancerModel><Cancers><Carcinogens><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Cellular injury><Chemokine (C-X-C) Receptor 2><Chronic><Collaborations><Colon><Combined Modality Therapy><Credentialing><DNA><DNA Damage><DNA Injury><Data><Dedications><Deoxyribonucleic Acid><Deposit><Deposition><Development><Dextrans><Diagnosis><Disease><Disorder><Dorsum><Dysfunction><Education><Educational aspects><Elderly><Excision><Exposure to><Extirpation><FITC><Feces><Fluorescein-5-isothiocyanate><Functional disorder><Future><GI microbiome><GI microbiota><GRO/MGSA Receptor><Gastrointestinal microbiota><Genetic><Genetic Models><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><High Affinity Interleukin 8 Receptor Type B><IL-8RB><IL-8Rbeta><IL8 Receptor Type 2><Immune><Immune mediated therapy><Immune system><Immunes><Immunologically Directed Therapy><Immunotherapy><Incidence><Inflammaging><Inflammation><Inflammatory><Innate Immune System><Interleukin 8 Receptor Beta><Interleukin 8 Receptor Type 2><Interleukin-8 Receptor Type B><Interleukin-8 Receptors B><Interleukin-8B Receptor><Intervention><Intervention Strategies><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal permeability><Intracellular Communication and Signaling><K22 Award><LPS-binding protein><LYT3><Leadership><Life><Link><Lipopolysaccharides><Liver><Macrophage><Malignant Bladder Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Marrow Neutrophil><Marrow monocyte><Measures><Mediating><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Monitor><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mφ><Neutrophil Activation><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Nitrosamines><Oncogenesis><Oncogens><Operative Procedures><Operative Surgical Procedures><Outcome><Oxidases><Oxygen Radicals><Patients><Phenotype><Physiopathology><Plasma><Plasma Serum><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Principal Component Analyses><Principal Component Analysis><Pro-Oxidants><Production><Public Health><Reactive Oxygen Species><Recurrence><Recurrent><Regulatory T-Lymphocyte><Removal><Research><Resolution><Reticuloendothelial System, Serum, Plasma><Risk><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T-Stage><Time><Tissues><Translations><Transplantation><Treg><Tumor Immunity><Tumor Volume><Tumor stage><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Weight><advanced age><age associated><age associated alterations><age associated changes><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age linked><age related><age related alterations><age related changes><age specific><age specific alterations><age specific changes><age-related inflammation><aged><aged animal><aged animals><aged mice><aged mouse><aging associated><aging associated disease><aging associated mechanism><aging mechanism><aging pathway><aging related><aging related disease><aging related mechanism><alterations with age><animal old age><anti-tumor immunity><antitumor immunity><bacteria in the gut><beta diversity><biological mechanism of age><biological pathways of age><biological signal transduction><cancer immunity><cancer microenvironment><cancer progression><career><cell damage><cell injury><cellular damage><changes with age><chemotherapy><co-morbid><co-morbidity><combination therapy><combined modality treatment><combined treatment><comorbidity><comparative><cytokine><damage to cells><developmental><dextran><digestive tract microbiome><disease of aging><disorder of aging><elderly animal><elderly mice><elderly patient><enteric microbial community><enteric microbiome><enteric microbiota><fecal microbial transplantation><fecal microbiome><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><gastrointestinal microbial flora><gastrointestinal microbiome><geriatric><gut bacteria><gut commensal><gut community><gut flora><gut health><gut homeostasis><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><hepatic body system><hepatic organ system><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><indexing><inflamm-ageing><inflamm-aging><inhibitor><injury to cells><injury to tissue><intervention effect><interventional strategy><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><juvenile animal><lipopolysaccharide-binding protein><malignancy><microbial><microbial consortia><microbial flora><microbiome><microbiota><microflora><monocyte><mouse model><multi-modal therapy><multi-modal treatment><multispecies consortia><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><neutrophil><novel><old animals><old mice><older patient><oncogenic agent><pathogen><pathophysiology><pharmacologic><prevent><preventing><recruit><regulatory T-cells><resection><resolutions><risk stratification><senior citizen><social role><standard of care><stool><stool microbiome><stool-associated microbiome><stratify risk><surgery><tissue injury><translation><transplant><tumor><tumor microenvironment><tumor progression><tumorigenesis><tumorigenic><urinary bladder><weights><young animal>