3D model of colorectal cancer organoids
Colorectal cancer (CRC) is the third most common malignancy worldwide, while it is the second most prevalent cancer for both males and females in Saudi Arabia. Intrinsic or acquired resistance to chemotherapy treatments - due to high inter- and intra-patient tumor genetic variability - causes 90% fatal disease relapse in patients already progressed to the metastatic stage. Therefore, the “one serves all” treatment principle is outdated and does not reflect our current knowledge of genetically-impacted patient-to-patient heterogeneity. Given the severity of the disease and its impact on society, there is an urgent need to develop a platform that will allow for advancing molecular and drug screening protocols for patients, in an effort to reach personalized treatment and to advise the medical staff.
In this project, we aim to initiate the establishment of the first organoid platform for personalized genetic and drug screening in Saudi Arabia, based on 3D scaffolds made of own-developed ultrashort self-assembling peptides. We will use them in an organ-on-a-chip (OoC) system that will allow high-throughput screening of CRC constructs derived from patients’ samples under varying conditions. This system will allow the study of the genome and transcriptome for data analysis and modeling of the dynamics of the CRC microenvironment. We will develop a genetic database for risk variants within the Saudi population, and use the OoC to model the effects of drugs in CRC organoids.
Once this platform is established, we will recreate in vitro the unique genetic background and tissue complexity of individual Saudi patients. All these technologies, the biomimetic peptides, the OoC system, the in silico modeling, and the genome/transcriptome analysis, will allow the further development of personalized medicine tools focusing on CRC molecular characteristics within the Saudi population.
In summary, based on our experience in tissue engineering, biomaterial design, and in silico approaches, together with a strong team of medical doctors, and colorectal cancer biologists, we will investigate the capability of our self-assembling bioactive peptides for genetic and phenotypic 3D organoid cultures and their application in reliable personalized medicine, specifically when using OoCs as screening systems.
Biological and Environmental Sciences and Engineering
Field of Study -
Tissue Engienerring, bioengineering, materials science
Charlotte A. E. Hauser
Professor, Bioengineering <br/>Chair, Bioengineering Program
Professor Hauser’s research interests align at the interfaces between chemistry, biomedicine, bioengineering and nanotechnology. Focus is on the development of platform technologies, using smart nanomaterials for regenerative, biomedical and environmental applications.
Her interest refers to the rational molecular design, synthesis and mechanistic understanding of novel supramolecular structures. Investigated systems include peptide-based nanostructures with an innate propensity to self-assemble to biomimetic architectures applicable for biomedical applications such as cell substrates, sensors and 3D tissue scaffolds for regenerative medicine. Bottom-up nanofabrication is a powerful tool for the development of functional tissue equivalents, organotypic tissues and devices. Moreover, these biomimetic supramolecular constructs will be used for the design and fabrication of novel organ-on-a-chip devices and disease models.
Furthermore, Professor Hauser is interested in 3D bioprinting, using supramolecular organotypic constructs to fabricate high-throughput platforms for drug screening, pathogen detection and other diagnostic purposes. Synthetic biology approaches are explored for the generation of functional biomaterial.
Desired Project Deliverables
The general objective of this project is to establish colon organoid cultures starting from tissue material derived from the Saudi Arabian population cultured in 3D SAP smart scaffolds and to prove their use for personalized drug screening. Our first goal will be to generate a library of biofunctional SAPs and formulate an SAP-based hydrogel that accommodates the mechanical and biochemical properties needed for PDX-derived organoid development. We will evaluate the “organoid-formation capacity” using PDX-derived organoids and validate the transcriptome and exosome landscape of the PDX-organoids cultured within our novel biomaterial. At the same time, we will couple this material to a bioprinting system that will minimize the human manipulation of constructs. Next, we will use such technologies to fabricate PDOs from a Saudi cohort of patients with colorectal cancer. Finally, we will screen the genetic markers of CRC within the patient samples and assess appropriate chemotherapies within our system. The project is divided into Phases I-III with the following objectives described as individual tasks: