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Principal Investigator: PHILLIP L PALMBOS
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $429,017
Funding agency: National Cancer Institute
Over 17,000 will die from bladder cancer in the U.S. this year. While most patients with noninvasive tumors are
cured, most patients with muscle-invasive disease will develop metastases and die. Therefore, understanding
and targeting the molecular driver(s) which facilitate this invasive switch is essential to improve patient
outcomes. TRIM29 is a critical driver of bladder cancer initiation, invasion and therapeutic resistance in human
tumors and mouse models. TRIM29 promotes tumor formation by regulating protein interactions that govern
beta-catenin and miRNA activity. TRIM29 impacts therapeutic resistance by regulating ubiquitination of DNA
repair and innate immune pathways. The specific mechanism by which TRIM29 drives invasive progression
remains poorly understood. Rationale: Emerging evidence from our lab has identified a novel function of
TRIM29 in the regulation of intermediate filaments, focal adhesion and FAK/Src signaling. However, we do not
yet understand how this TRIM29-focal adhesion axis is regulated, how it participates in progression from non-
invasive to invasive cancers in vivo or how it coordinates with previously identified mechanisms to promote
invasive progression. This is a critical gap in knowledge because without a clear understanding of these
events, we are unable to develop therapeutic strategies to target this pathway and prevent progression to the
lethal invasive form of bladder cancer. The specific objective of this proposal is to identify the role of this novel
TRIM29-focal adhesion axis in invasive progression and to use this knowledge to develop therapeutic
strategies to block invasive progression in high-risk TRIM29+ tumors. The central hypothesis is that TRIM29
drives progression from noninvasive to lethal invasive bladder cancer by driving intermediate filament
and focal adhesion formation, and activation of FAK/Src signaling in invasive cells. This hypothesis will
be tested in the following specific aims: 1) To conduct detailed structure-function analysis of the TRIM29
interaction with intermediate filaments, the focal adhesion complex, and FAK/Src signaling during invasion. 2)
To determine the requirement for TRIM29, KRT14, and focal adhesion proteins during bladder cancer initiation
and invasive progression. 3) To evaluate novel therapeutic strategies to block TRIM29-mediated invasion in
bladder cancer. Aim 1 will utilize live cell imaging, 3D and animal models of invasion. Aim 2 will leverage
unique GEMM of bladder cancer to dissect the essential functions of TRIM29 in vivo. Aim 3 will use our
multiple models to identify therapeutic strategies to target TRIM29-mediated invasion. This research is
conceptually innovative in the characterization of a novel TRIM29-focal adhesion pathway of invasive
progression and technically innovative in the development of novel bladder cancer murine models, advanced
3D tumor invasion assays and novel therapeutic targeting strategies. The proposed research is significant
because description of the mechanism of TRIM29-mediated invasive progression will allow identification of
novel therapeutic strategies to block development of lethal invasive progression in bladder cancer.
Terms: <3-D><3-D modeling><3-Dimensional><3D><3D modeling><ASVSRC1><Adhesion Plaques><Animal Model><Animal Models and Related Studies><Area><Assay><Automobile Driving><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Bioassay><Biological Assay><Biology><Bladder Cancer><Bladder Neoplasm><Bladder Tumors><CUL-2><Cancer Model><CancerModel><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Matrix Adherens Junctions><Cells><Clinical><Complex><DNA Damage Repair><DNA Repair><Development><Diagnosis><Disease><Disorder><Drugs><Early Diagnosis><Early identification><Event><FADK><FAK><FAK1><Focal Adhesions><Focal Contacts><Gene Modified><Genetic Alteration><Genetic Change><Genetic defect><Goals><Human><Immune><Immunes><Intermediate Filaments><Intracellular Communication and Signaling><Invaded><Keratin><Knowledge><Local Therapy><Localized Therapy><Malignant Bladder Neoplasm><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Micro RNA><MicroRNAs><Mission><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Molecular Target><Muscle><Muscle Tissue><Mutation><Neoplasm Metastasis><Oncogenic><Outcome><PRO2286><PTK2><PTK2 gene><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Persons><Pharmaceutical Preparations><Prevention><Process><Proteins><Public Health><RBCC/TRIM Motif><Regulation><Relapse><Research><Risk><Role><SRC Family Gene><SRC gene><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Structure><TRIM Motif><Testing><Therapeutic><Therapeutic Intervention><Tripartite Motif><Tumor Cell Invasion><Tumor Invasion><Tumor Promotion><Ubiquitilation><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitination><Ubiquitinoylation><United States><Unscheduled DNA Synthesis><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Urinary Bladder Neoplasm><Urinary Bladder Tumor><beta catenin><biological signal transduction><biomarker identification><c src><c-src Genes><c-src Proto-Oncogenes><cancer initiation><cancer invasiveness><cancer metastasis><cancer progression><conformation><conformational><conformational state><conformationally><conformations><developmental><driving><drug/agent><early detection><gene modification><genetically modified><genome mutation><high risk><human disease><identification of biomarkers><identification of new biomarkers><improved><in vivo><inhibitor><innate immune pathways><innovate><innovation><innovative><insight><interest><intervention therapy><live cell image><live cell imaging><live cellular image><live cellular imaging><marker identification><miRNA><miRNAs><model of animal><mortality><mouse model><murine model><muscle invasive bladder cancer><muscular><neoplasm progression><neoplastic progression><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pathway><patient oriented outcomes><paxillin><pp125FAK><prevent><preventing><progression risk><resistance to therapy><resistant to therapy><scaffold><scaffolding><social role><therapeutic resistance><therapeutic target><therapy resistant><three dimensional><three-dimensional modeling><treatment resistance><tumor><tumor cell metastasis><tumor initiation><tumor progression><ubiquination><ubiquitin conjugation><ubiquitin ligase><v-SRC Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene Homolog><β-catenin>