Patient-derived organoids as a platform for modeling a patient’s response to chemoradiotherapy in esophageal cancer

Karakasheva, Tatiana A.; Gabre, Joel; Sachdeva, Uma M.; Cruz‐Acuña, Ricardo; Lin, Eric W.; DeMarshall, Maureen; Falk, Gary W.; Ginsberg, Gregory G.; Yang, Zhaohai; Kim, Michele M.; Diffenderfer, Eric; Pitarresi, Jason R.; Li, Jinyang; Muir, Amanda B.; Hamilton, Kathryn E.; Nakagawa, Hiroshi; Bass, Adam J.; Rustgi, Anil K.

doi:10.1038/s41598-021-00706-8

Cited by 35 publications

(33 citation statements)

References 20 publications

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“…Enzymatically and mechanically dispersed patient-derived esophageal cancer biopsies were serially cultured as organoids for multiple passages, indicating self-renewal and expansion potential of cancer stem cells ( Figure 5 A,B). Furthermore, the ec-PDOs stained positive for the EAC marker MUC5AC [ 30 , 31 ], suggesting an EAC origin ( Supplementary Figure S5 ).…”

Section: Resultsmentioning

confidence: 99%

Role of mTOR through Autophagy in Esophageal Cancer Stemness

Wang

Nagle

et al. 2022

Cancers

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Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44+/CD24−), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44+/CD24− population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44+/CD24− population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44+/CD24− CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs.

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Section: Resultsmentioning

confidence: 99%

Role of mTOR through Autophagy in Esophageal Cancer Stemness

Wang

Nagle

et al. 2022

Cancers

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“… 129 Endoscopic biopsy of esophageal cancer generates PDO and compares clinical outcomes after neoadjuvant therapy with in vitro PDO responses. 325 Organoids from metastatic CRC and GC/EAC PDOs have been used for mid-range drug screening, and parallel drug studies in organoid xenografts confirm in vitro and in vivo therapeutic response correlations. 324 The response of GC PDOs to two clinically used paclitaxel (PTX) nanoformulations, albumin-bound PTX (Albu-PTX) and liposomal PTX (Lipo-PTX), was comparatively assessed using a GC PDO model that reproduced the therapeutic superiority of Lipo-PTX over Albu-PTX.…”

Section: Digestive System Organoid Models and Precision And Personali...mentioning

confidence: 98%

Applications of human organoids in the personalized treatment for digestive diseases

Wang

Guo

Jin

et al. 2022

Sig Transduct Target Ther

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Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

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“…Moreover, the PDO-based prediction model is expected to be applicable to other solid tumors. For instance, PDOs have been reported to predict the response of patients with esophageal cancer to neoadjuvant CRT [ 89 ]. Methods other than PDO have been found to be associated with a relatively low prediction accuracy; for example, predicting the effect of CRT based on imaging findings showed an accuracy of 30–60%, and serum biomarkers showed an accuracy of approximately 70% [ 90 , 91 ].…”

Section: Patient-derived Organoids As Predictive Biomarkers In Cancer...mentioning

confidence: 99%

Patient-Derived Organoids of Colorectal Cancer: A Useful Tool for Personalized Medicine

Kiwaki

Kataoka

2022

JPM

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Colorectal cancer is one of the most important malignancies worldwide, with high incidence and mortality rates. Several studies have been conducted using two-dimensional cultured cell lines; however, these cells do not represent a study model of patient tumors very well. In recent years, advancements in three-dimensional culture methods have facilitated the establishment of patient-derived organoids, which have become indispensable for molecular biology-related studies of colorectal cancer. Patient-derived organoids are useful in both basic science and clinical practice; they can help predict the sensitivity of patients with cancer to chemotherapy and radiotherapy and provide the right treatment to the right patient. Regarding precision medicine, combining gene panel testing and organoid-based screening can increase the effectiveness of medical care. In this study, we review the development of three-dimensional culture methods and present the most recent information on the clinical application of patient-derived organoids. Moreover, we discuss the problems and future prospects of organoid-based personalized medicine.

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Patient-derived organoids as a platform for modeling a patient’s response to chemoradiotherapy in esophageal cancer

Cited by 35 publications

References 20 publications

Role of mTOR through Autophagy in Esophageal Cancer Stemness

Role of mTOR through Autophagy in Esophageal Cancer Stemness

Applications of human organoids in the personalized treatment for digestive diseases

Patient-Derived Organoids of Colorectal Cancer: A Useful Tool for Personalized Medicine

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