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Review
. 2021 Jul 13:9:674219.
doi: 10.3389/fcell.2021.674219. eCollection 2021.

Future Match Making: When Pediatric Oncology Meets Organoid Technology

Virginie Barbet  1 , Laura Broutier  1
Affiliations
Review

Future Match Making: When Pediatric Oncology Meets Organoid Technology

Virginie Barbet et al. Front Cell Dev Biol. .

Abstract

Unlike adult cancers that frequently result from the accumulation in time of mutational "hits" often linked to lifestyle, childhood cancers are emerging as diseases of dysregulated development through massive epigenetic alterations. The ability to reconstruct these differences in cancer models is therefore crucial for better understanding the uniqueness of pediatric cancer biology. Cancer organoids (i.e., tumoroids) represent a promising approach for creating patient-derived in vitro cancer models that closely recapitulate the overall pathophysiological features of natural tumorigenesis, including intra-tumoral heterogeneity and plasticity. Though largely applied to adult cancers, this technology is scarcely used for childhood cancers, with a notable delay in technological transfer. However, tumoroids could provide an unprecedented tool to unravel the biology of pediatric cancers and improve their therapeutic management. We herein present the current state-of-the-art of a long awaited and much needed matchmaking.

Keywords: cancer; genetic engineering; heterogeneity; modeling; organoids; pediatric cancer and oncology; plasticity; tumoroids.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Landmark studies in cancer model discovery. The history of cancer models can be retraced back to the early 1900s, when Harrison described the first tissue culture technique and when Carrel and Burrows defined a basic protocol to standardize the in vitro culture of human malignant tumors. Thereafter, the development of these cell culture techniques generated the first human cell line derived from a patient (HeLa) in 1951 and the Raji cell line, as one of the first pediatric cancer cell lines in 1963. In parallel with these in vitro models, many animal cancer models emerged following the discovery of tumors in drosophila in 1918, the first xenografts of human tumor in chorioallantoic membrane (CAM) of chick embryo in 1918, in immune-repressed rodents in 1953, or in zebrafish in 2006, and the generation of genetically engineered animal cancer models. Later, in order to recreate a cancer model closely mimicking the histological complexity and genetic heterogeneity of human cancers, the first tumoroids derived from a patient tumor tissue were described by Sato et al. in 2011. The first tumoroids were then engineered from normal human tissue-specific SCs and the generation of an organoid biobank for a pediatric cancer was described. Yellow boxes highlight pediatric cancer models.
FIGURE 2
FIGURE 2
Flowcharts of the establishment of pluripotent stem cell (PSC)-derived and tissue-specific stem cell (tSC)-derived organoids. Organoids can be established from PSCs (iPSCs and ESCs) or tissue-specific SCs (tSCs; left-hand box). Two key steps are involved in PSC-derived and tSC-derived organoid production. First (central box), the identification of crucial cell signaling pathways allowing directed differentiation (combinations of morphogens and growth factors) and/or to establish a permissive environment for the stem cell culture by mimicking their in vivo niche (specific growth factors and inhibitors). Second (right-hand box), cultures are grown so as to favor their expansion in three dimensions, which is achieved either by aggregating cells into 3D structures or by embedding the cultures into a 3D matrix scaffold.
FIGURE 3
FIGURE 3
Schematic diagram depicting current methods for generating tumoroids. Tumoroids can be established from PSCs (iPSC and ESC), tissue-specific SCs (tSCs), and directly from tumor biopsies, resection, or fluids (left-hand box). Similar to organoids, two key steps are involved in tumoroid derivation. Following genetic engineering (for PSCs and tSCs) and directed differentiation in a specific cell lineage by morphogens (for PSCs), identification of key cell signaling pathways to mimic CSC niche factors (growth factors and inhibitors) allows tumoral cells to be cultured in three dimensions (aggregation or matrix scaffold; central and right-hand boxes).
FIGURE 4
FIGURE 4
Tumoroid reconstruct inter- and intra-tumoral hierarchy and dynamics. Tumoroids can be used to evaluate the importance of tumor heterogeneity: inter-tumoral heterogeneity in which tumors of the same type but from different patients have distinct clinical features, and intra-tumoral heterogeneity in which different populations within a tumor have divergent genotypes and phenotypes. Indeed, in this case, different subclones (represented by different colors) emerge due to multiple oncogenic events from a common ancestor (cell-of-origin). Cancer stem cells (CSCs) that arise from these events can self-renew and produce various cell lineages present in a tumor (different cell states from each subclone are represented in respective colors). This intra-tumoral heterogeneity can be affected by the tumor microenvironment and collaboration between tumor cells.
FIGURE 5
FIGURE 5
Potential applications of tumoroids in the field of cancer research. Tumoroids can be derived from PSCs and tissue-specific SCs after introduction of cancer-associated genetic alterations, or directly from tumor samples. These resulting tumoroids represent cancer models and can be profiled by multi-omics integrative analyses to decipher new oncogenetic processes. In basic research, tumoroids can be used to study cancer initiation and its related processes such as the understanding of the cell-of-origin and the links between tumorigenesis and infectious agents or environmental factors. In addition, tumoroids can be used to identify the biological underpinnings of tumor progression and resistance to treatments. Biobanks of tumoroids, in which samples obtained from patients are stored as a resource for future research, can promote the discovery of new cancer drugs and guide optimized therapeutic strategies for an individual or group of stratified patients by predicting drug responses. To conclude, tumoroids have the potential to translate scientific knowledge from bench to bedside with scientific discoveries being swiftly returned to the patient.
FIGURE 6
FIGURE 6
Tumoroid as a promising tool for understanding and treating pediatric cancer. Tumoroid technology can be exploited to model germline pediatric cancer predisposition syndrome, to study origins of cancers (A) and to perform multi-omic profiling analyses (B) in order to promote the understanding of pediatric cancer biology. In addition, tumoroids can be used to identify the biological underpinnings of cell death resistance such as tumoral cells state dynamics and collaboration (C) and to perform drug-screening analyses based notably on phenotypic screens (D) to explore innovative and powerful therapeutic possibilities.
FIGURE 7
FIGURE 7
Strengths and weaknesses of organoids in cancer modeling. Organoids are assessed here for their relative benefits and limitations for cancer research by comparison with other model systems. Respective features are rated as best, good, partly suitable, and unsuitable. By bridging the gap between conventional 2D culture and animal models, organoids provide a unique opportunity to deal with a moderate system complexity meanwhile capturing the complexity of tumors. N/A, non-applicable.
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