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Principal Investigator: Priya Harakh Dedhia
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $206,689
Funding agency: National Cancer Institute
Adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor 5-year survival rate of 6% for patients
with metastatic disease. There are no targeted therapies for these patients. Unfortunately, current treatments
only slow disease progression for an average of 5 months, after which drug resistance quickly develops. As
such, there is a critical need to identify new targets of intervention and develop new treatments for ACC. ACC
can be characterized by significant heterogeneity both intertumorally between patients and intratumorally within
an individual tumor, making choosing an effective therapeutic strategy challenging. Several mechanistic
pathways have been identified that may correlate with disease progression: IGF2, Wnt/β-catenin (Wnt), and cell
cycle regulating pathways such as p53/retinoblastoma protein (Rb) are dysregulated in 90% of ACC, and
correlate with metastatic disease. Unfortunately, the intratumoral heterogeneity of IGF2, Wnt, and p53/Rb
dysregulation and its contributions to ACC tumor progression is unknown, although each of these pathways has
been implicated or correlated with tumor invasion, matrix metalloproteinase (MMP) expression, or metastasis in
other cancers. This lack of understanding can partially be attributed to the lack of appropriate preclinical research
models. Most attempts to generate ACC models have been unsuccessful. The small number of existing models
do not adequately reflect the oncogenic signaling pathways and intratumoral heterogeneity of human ACC. A
human-based ACC model system permitting functional and transcriptomic characterization of tumor
subpopulations following metastasis does not exist. To address these critical research gaps, we developed the
first patient-derived organoids (PTOs) from patient samples as well as an ACC metastasis-on-a-chip (MOC)
platform. Our MOC platform is an in vitro microfluidic system that incorporates tumor organoids, recirculating
fluid flow, and downstream tissue organoids, which can recapitulate aspects of metastasis from a primary tumor
site to metastatic sites. In addition, we have developed MMP peptide biosensor technology that integrates into
our organoids, enabling near-real time observation of MMP-mediated tumor cell invasion. We will deploy this
platform to sort tumor cells into metastatic/motile versus non-metastatic/less motile subpopulations for analysis
of expression of dysregulated pathways in ACC (IGF2, Wnt, and p53/Rb) and subpopulation heterogeneity
determined by single cell RNA sequencing. We hypothesize that IGF2, Wnt, and cell cycle dysregulation
correlates with increased metastasis kinetics and MMP activity in ACC PTOs deployed in our MOC platform.
Towards this hypothesis: Aim 1 will delineate metastasis kinetics, MMP activity, and proliferation of ACC PTO
cells; Aim 2 will define ACC intratumoral heterogeneity of critical oncogenic pathway dysregulation using single
cell-RNA-sequencing; Aim 3 will determine the relative importance of each driver pathway on metastatic potential
through drug-based inhibition. Upon completion of this project, we aim to both better understand ACC disease
biology and have an established model of ACC that can be deployed for preclinical studies.
Terms: <3-D><3-Dimensional><3D><Address><Adrenal Cortex Carcinoma><Adrenal Cortical Carcinoma><Adrenocortical Carcinoma><Animal Model><Animal Models and Related Studies><Antioncogene Protein p53><Beta Cadherin-Associated Protein><Beta-1 Catenin><Biologic Models><Biological><Biological Models><Biology><Biosensing Technics><Biosensing Techniques><Biosensor><Body Tissues><CUL-2><Cancers><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Cycle Control><Cell Cycle Regulation><Cell Division Cycle><Cell Growth in Number><Cell Isolation><Cell Line><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Proliferation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><CellLine><Cells><Cellular Migration><Cellular Motility><Cellular Proliferation><Cellular Tumor Antigen P53><Circulation><Clinical><Complex><Confocal Microscopy><Data><Devices><Disease><Disease Progression><Disorder><Distant><Drug resistance><Drugs><ECM><Event><Extracellular Matrix><Failure><Foundations><Frequencies><Future><Heterogeneity><Human><Hydrogels><IGF2><IGF2 gene><In Vitro><Individual><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intratumoral heterogeneity><Kinetics><Label><Liver><Lung><Lung Respiratory System><MMPs><Malignant Neoplasms><Malignant Tumor><Matrix Metalloproteinases><Mediating><Medication><Metastasis><Metastasize><Metastatic Carcinoma><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Microscopy><Model System><Modeling><Modern Man><Motility><Neoplasm Metastasis><Non-metastatic><Nonmetastatic><Oncogenic><Oncoprotein p53><Organoids><P105-RB><P53><PP110><PRO2286><Pathway interactions><Patients><Peptides><Pharmaceutical Preparations><Phosphoprotein P53><Phosphoprotein pp53><Pre-Clinical Model><Preclinical Models><Prediction of Response to Therapy><Primary Neoplasm><Primary Tumor><Proliferating><Property><Protein TP53><Rb Gene Product><Rb Protein><Rb1 Gene Product><Research><Resistance><Retinoblastoma Associated Protein><Retinoblastoma Protein><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Site><Sorting><Strains Cell Lines><Survival Rate><System><TP53><TP53 gene><TRP53><Technology><Therapeutic Intervention><Time><Tissues><Tumor Cell><Tumor Cell Invasion><Tumor Invasion><Tumor Protein p53><Tumor Protein p53 Gene><Work><beta catenin><biologic><biological sensor><biological signal transduction><biosensing><cancer metastasis><cancer progression><cell motility><cell sorting><cell type><cultured cell line><drug resistant><drug sensitivity><drug/agent><effective therapy><effective treatment><fluid flow><hepatic body system><hepatic organ system><heterogeneity in tumors><imaging Segmentation><in vivo><inhibitor><insight><intervention therapy><interventional strategy><intra-tumoral heterogeneity><intratumor heterogeneity><malignancy><microfluidic chip><migration><model of animal><mouse model><murine model><mutation status><mutational status><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pRB><pathway><pre-clinical research><pre-clinical study><preclinical research><preclinical study><predict therapeutic response><predict therapy response><protein p53><pulmonary><resistance to Drug><resistant><resistant to Drug><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><therapeutically effective><therapy prediction><three dimensional><transcriptomics><treatment prediction><treatment response prediction><tumor><tumor cell metastasis><tumor heterogeneity><tumor progression><µfluidic><β-catenin>