The Origins of Organoids
Organoids are derived from different types of stem cells, such as pluripotent stem cells (PSCs) or multipotent organ-specific adult stem cells (ASCs). The choice of starting point leads to key differences between the resulting organoids and their applications, which is notably seen in oncology research and drug development.
The Main Differences Between PSC- and ASC-Derived Organoid Development
PSC-derived organoids are typically obtained from embryonic stem cells or induced-PSCs (iPSCs). A multistep process is needed to generate organoids from iPSCs which requires reprogramming and redifferentiation of the stem cells into the appropriate lineage, depending on the tissue of interest (endoderm, mesoderm, or ectoderm). This also requires a specific cocktail of factors and a mesenchymal cell niche to direct PSC differentiation into the desired cell fate, as well as a passage through spheroid culture before development into organoids. iPSCs are extensively used to derive brain organoids to study organ development and pathology.
In contrast, ASC-derived organoids are developed from tissue-specific stem cell populations. ASCs are grown in the absence of a mesenchymal cellular niche. Their development is supported by the presence of growth factors that allow for their self-renewal and differentiation into all the downstream cell types present in the parental organ. This ASC process was made possible by seminal discoveries from the Clevers lab, who initially discovered ASCs in the small intestine. They were also the first to develop mini guts in a dish. Subsequent research showed that ASCs exist in other organs of epithelial origin, such as the stomach, liver, and pancreas.
Hubrecht Organoid Technology (HUB) expanded upon and optimized this technology to develop 3D organoids from both healthy and diseased tissue, which includes tumor organoids. HUB technology produces robust and reproducible organoid models that preserve original organ genetics and gene expression features over several generations. This is a faster approach to organoid development, as ASC don´t require reprogramming to differentiate into the appropriate lineage. Additionally, the absence of a mesenchymal niche contributes to generating more robust models, as mesenchymal cells can affect the stability of the culture over time.
HUB Technology Is the Only Tumor Organoid Platform
The most important distinction between ASC- and iPSC-derived organoids is their application within cancer research.
ASC derived organoids, unlike the iPSC counterparts, are derived from both healthy and cancer patient tissue. Using HUB’s refined protocols and culture media, tumor organoids have been established from various carcinomas. These organoids were developed from tumor patient material and used to establish biobanks of tumor (and matched healthy) organoids that capture the phenotypic and genetic heterogeneity in cancer patient populations.
PSCs can be genetically engineered to introduce oncogenic or tumor suppressor mutations. This generates tumor-like growths, but these models lack the complexity of the genetic make-up of each clinical tumor, that can only be recapitulated starting from patient material.
This is why tumor organoids developed using HUB technology are the only clinically relevant organoid models available for oncology drug development, specifically for epithelial cancer.
Using HUB Tumor Organoids for Oncology Drug Development
The development of large living biobanks of tumor organoids developed using HUB protocols allows you to bring ‘patients to the lab’. These tumor organoids are used to conduct large scale population studies investigating treatment response and to identify biomarkers. This approach is the equivalent of a clinical trial but carried out in a dish, therefore expediting drug development and reducing the high attrition rate of oncology candidates.
While organoids can be established using different types of stem cells, HUB technology is the only tumor organoid platform available for solid epithelial cancer drug development. Tumor organoids from HUB technology are highly patient relevant and can be used to develop biobanks that enable “clinical trials in a dish.”