Current and Future Perspectives of the Use of Organoids in Radiobiology

Abstract

The majority of cancer patients will be treated with radiotherapy, either alone or together with chemotherapy and/or surgery. Optimising the balance between tumour control and the probability of normal tissue side effects is the primary goal of radiation treatment. Therefore, it is imperative to understand the effects that irradiation will have on both normal and cancer tissue. The more classical lab models of immortal cell lines and in vivo animal models have been fundamental to radiobiological studies to date. However, each of these comes with their own limitations and new complementary models are required to fill the gaps left by these traditional models. In this review, we discuss how organoids, three-dimensional tissue-resembling structures derived from tissue-resident, embryonic or induced pluripotent stem cells, overcome the limitations of these models and thus have a growing importance in the field of radiation biology research. The roles of organoids in understanding radiation-induced tissue responses and in moving towards precision medicine are examined. Finally, the limitations of organoids in radiobiology and the steps being made to overcome these limitations are considered.

Complete response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT mutations and high tumour mutational burden

“…Current cell lines have a bias towards their micro environment and although provide reasonable models of single pathway alterations lack the fidelity to measure therapy response when modulated. The ideal model would be an organoid based rectal cancer therapy model [60] as this provides both the 3D structure (enabling cell/cell communication a more representative element of intratumoural hypoxia) and more accurate response to therapy, as well as the ability to evolve and resist therapy and the ability to co-culture with other cells in the microenvironment such as T-cells and fibroblasts.…”

Models for Translational Proton Radiobiology—From Bench to Bedside and Back

“…Another level of complexity is achieved by establishing patient-derived organoids from normal and tumor tissues of various entities [118][119][120][121][122][123]. They are considered the culture models closest to the individual patient, mirroring the heterogeneity and genetic background of the original tissue [124,125]. Organoids can also be grown from mouse tissue, which opens a wide range of possibilities for biological studies, including the use of transgenic donors [126,127].…”

“…Furthermore, Brack et al recently proved the technical feasibility of their irradiation device with laserdriven particles by visualizing DNA damage in a spheroid model [72]. Organoids derived from stem or progenitor cells are of utmost relevance for investigating normal tissue side effects, as they allow for stem cell-related response studies [125]. Normal tissue organoids, originating from, for example, the intestinal system, the salivary glands, or the mammary glands, were used to assess tissue radiation sensitivity and irradiation-induced toxicity mechanisms [127,[140][141][142].…”

“…Here, patient-derived organoids represent a powerful tool for individualized treatment decisions [122,128]. Future trials should include pairs of normal and cancer tissue-derived organoids from the same patient to evaluate the full range of individual therapeutic windows [125,128].…”

Stem Cells and Irradiation

“…Integration of the cross talk of these two types of stem cells is essential. Nagle and colleague studied the roles of organoids as model to understand relationship between normal tissue and tumor responses in radiobiological studies [ 1 ]. Understanding the radioresistance mechanisms of cancer cells is fundamental in order to be able to eradicate the tumor while preserving healthy tissue.…”