Organoids

Patient-derived organoids offer a unique system for molecular target discovery and development.

Multiple studies have demonstrated that organoids faithfully retain biological characteristics of the tissues from which they are derived.

In the case of many normal tissues, organoids retain the cell types present in situ as well as the ability to undergo functional differentiation. In the context of disease, especially cancer, organoids retain the molecular and morphological heterogeneity of the originating tumor as well as the drug sensitivity and resistance profile seen in the original patient. This is the case for both conventional and targeted therapies; thus, organoid culture conditions retain the original target profile and signaling networks seen in patients.

Organoids also have the advantage that they are readily amenable to genetic manipulation for target modulation, with overexpression, CRISPR/cas9 and shRNA techniques established in these systems. In addition to in vitro analysis, organoids can also be used to test drug targeting in vivo. Tumor organoids can be grown as xenografts that histologically mirror the originating tumor and techniques are available for orthotopic engraftment of normal organoids for several tissues. Thus, organoids represent a physiologically relevant platform that can be readily manipulated for target identification and validation.

Based on the strong research potential of these systems, an organoids core is proposed for Phase 2. This core, which will build on the success of the organoid component of the Phase 1 Target Validation Core, is designed to facilitate the use of organoids by the center's investigators and the wider research community.

Developing, maintaining, and manipulating organoids requires an established infrastructure, considerable expertise and a substantial commitment of time and resources, creating significant barriers to the adoption of organoid systems by individual laboratories. By providing access to a bank of established patient-derived organoids, and the expertise, resources and reagents for culturing and manipulating these structures, the core will remove these barriers to the use of organoids.

The core will continue to support preliminary experiments that establish the applicability of organoids for investigators’ studies, while providing training and rea-gents to enable investigators to establish this technology in their own laboratories. The core currently holds normal and tumor patient-derived organoids from colon, rectum and small intestine, liver, breast, pancreas and prostate, and plans to expand to additional tissues and diseases as demand is identified.

The core also has generated organoids from a number of mouse models and will establish organoids from additional models upon request. The establishment of an extensive biobank containing normal and disease organoids from multiple tissues will provide a valuable resource for the research community at large.

Patient-derived organoids in the core will be associated with deidentified clinical data and will be genetically characterized, which will aid in identification of suitable models for hypothesis testing. Importantly, the core has been designed to store and distribute patient-derived organoids stripped of personal health information and use of these organoids has been designated as non-human subject research by the UNMC IRB. As a result, researchers do not have to obtain an approved IRB protocol to use organoids from the core, removing another significant barrier.

Based on the experience gained in Phase 1, the overall goal of the core under Phase 2 will be to develop a repository of extensively characterized organoids for use by COBRE investigators and the wider research community and to lend expertise and reagents to promote and support use of these models.

The Organoids Core will pursue the following aims:

• Aim 1: Expand and further characterize the existing Organoid Biobank.
• Aim 2: Support use of organoids by COBRE Research Project Leaders.
• Aim 3: Promote use of organoids in ongoing research of our center's investigators and the wider scientific community.