3.1.2. PDAC Organoid Cultures

To better address the lack of 3D structure and function of 2D models, 3D organoid (organ-like) structures may be used that self-organize into structures that more closely resemble the in vivo tissue structure, composition, and function [70]. To model PDAC, normal or cancerous pancreatic ductal cells are typically embedded in Matrigel™, which contains important components of basement membrane and growth factors. Pancreatic ductal cells form polarized structures due to the cell–cell contacts and cell-matrix interactions, which can greatly influence gene expression when compared to 2D cultures [71]. The ability to better mimic the complex 3D architecture of PDAC in vitro is a valuable platform for testing drug delivery, pharmacokinetics, efficacy, and drug resistance. One of the key advantages of the organoid model is the ability to study PDAC progression by comparing normal pancreatic, preneoplastic, and PDAC cell-based organoids. Better understanding at what phases PDAC is more susceptible or resistant to OV therapy is of particular interest to our group, and such a model represents an unparalleled system for controlled disease progression and visibility. Although organoids have many promising potential applications, there are still limitations. First, this organoid model system is synthetic and the mutational selection is not well understood [72]. Second, many of these models are solely epithelial tissue layers, lacking important elements of the tumor microenvironment such as immune cells, nervous cells, mesenchyme, muscular layers, etc. [73]. This limitation is addressed in more realistic organoid models of PDAC, or, "PDACoids" are additionally co-cultured with stromal components like cancer-associated fibroblasts (CAFs), PSCs, endothelial cells, and immune cells to better mimic the dense stroma which typically represents up to 90% of the tumor volume and is a major player in PDAC tumor progression and therapeutic resistance [74]. Thirdly, the organoid model fails to address the complex immune system dynamics as in the human disease [75]. Unfortunately, even as organoid models continue to progress towards the true complexity of the in vivo tumor, the immune microenvironment around a tumor is exceedingly difficult to truly recapitulate in vitro. Despite the limitations of organoids, this technology has great potential and use to more closely model human tumors. We would like to refer to a more exhaustive review of 3D cell culture approaches, including the spheroid model systems here [76].

PDAC organoid cultures offer a more realistic model to study OV delivery, replication, cell lysis, and oncoselectivity, as they better mimic the 3D organization and complexity of the human disease. Recent studies showed that an adenovirus-based OV exhibited good oncoselectivity, with replication only occurring in organoids from PDAC tumors. The group also concluded that the cytotoxicity observed in PDAC organoids was predictive of antitumor efficacy in both subcutaneous (SC) and orthotopic xenograft models [77]. Although VSV has not yet been tested in a PDAC organoid setting, other OVs used so far [64,78,79] have been promising and provide a more predictive model for in vivo disease.
