Organoids are ex vivo model systems that revolutionized basic and translational cancer research in the domain of disease biology, since last decade. Organoid 3D cultures undergo mitogen-mediated proliferation as multicellular structures in semisolid matrices and while they possess some similarities like 3D spheroid cultures of cell lines, there are basic fundamental differences between them (Tsai et al. 2018). Organoids enable both the proliferation of undifferentiated epithelial cells and generation of differentiated cell types, thereby providing the scope for control cells of the same lineage for comparative studies. In cancer research, organoids also allow culturing of pre-cancerous cells and thereby broadens scope of research on proto-oncogenes and cancer detection by 3D assays. Moreover, organoids can adjust with molecular and cellular characterization owing to genetic manipulation for studying cancer etiology and drug resistance.
Role In Studying Tumor Microenvironment
The most critical role of organoids in cancer research is to study tumor microenvironment for investigating tumor progression and hypoxia. The Tumor microenvironment deals with extracellular matrix (ECM) and the non-cancerous cell types surrounding the tumorous cell population. The communication between cancerous cells and the TME provides a niche for the tumor and opens up scope for novel therapeutics. Organoid cultures use matrix like Matrigel as extracellular matrix rich in proteins like laminin (Kleinman & Martin 2005). Currently, fully-defined synthetic matrix, as Matrigel substitutes, are being developed (Cruz-Acuna et al. 2017, Gjorevski & Lutolf 2017, Gjorevski et al. 2016).
The paracrine signaling interactions in case of tumors are intrinsic and challenging and thus complex structures like organoids, at times with cocultures of stromal cells, are used for research. Usui et al. (2016) used a myofibroblast-associated epithelial organoid system from resected human colorectal tumors to observe αSMA-positive myofibroblasts besides tumor epithelium. This system doesn’t put the cancer cells or tumor-associated myofibroblasts through selective pressures of monolayer cultures but as a limitation, it doesn’t distinguish the dissection of stromal-cancer signaling.
As an alternated model, Okawa et al. (2007) had developed an organoid system with esophageal epithelial cells on top of fibroblast-seeded Matrigel/collagen beds. In another model system, mitogen-driven organoid models are developed to promote epithelial expansion by stromal cells in an alternative culture medium (Ohlund et al. 2017). These models can be further improved by using more than one stromal cell types to co-culture with cancer cells and use as viable platforms for immunotherapies (using autologous immune cells and non-autologous immune cells) and other cancer therapies. Besides co-culturing and 3D assays, organoids also provide detailed ease in bioluminescent cell assays in complex culture models for studying tumor microenvironment.
Platform For Screening And Personalized Medicine
Organoids have been regarded as prominent models for establishing accurate methods for drug discovery and processing. Personalized medicine deals with the concept of each cancer patient being subjected to unique treatment regime based on their health concerns and dependencies. Thus, patient-derived organoids can be a crucial advantage as they can undergo empirical drug testing and molecular analyses with close to native tumor environment results. Recently, research have shown that organoids can mimic the responses of the patients, from whom the organoids were derived, and also showed remarkable responses to targeted and cytotoxic agents (van de Wetering et al. 2015, Steinhart et al. (2017). Since organoids greatly expand the research domain of cancer models beyond the monolayer cultures, it is justified that these models have discovered empirical new therapeutic targets such as ERK inhibition for primary liver cancer subsets (Broutier et al. 2017).
In 2018, a large organoid collection analysis from patients with refractory and metastatic colorectal and gastroesophageal cancer, showed the role of organoids in prediciting clinical outcomes and responses (Vlachogiannis et al. 2018). In another study, colorectal cancer organoids from treatment-naïve patients were reported to model intra-tumoral response variation to targeted therapies (Roerink et al. 2018). Research have also reported that patient-derived organoids were exceptional responders to therapies and were concordant with the molecular features and therapeutic characterization (Tiriac et al. 2018).
Organoids efficiently facilitate the fundamental and translational goals of cancer research with a vast expansion of the scope through which medical community looks at neoplasms and metastasis. Organoids represent the diverse human cancer spectrum and with more research and advancements, organoid culturing and matrix synthesis will improve further. In the near future, organoids will be extensively used for cancer research owing to their applications in carcinoma molecular profiling, personalilzed medicine, immunotherapies, drug kinetics, cancer detection, clinical outcomes, and novel therapeutic strategies for the cancer patients. For more information on organoids and the role of primary cells in organoid culturing, contact firstname.lastname@example.org