Challenges in Establishing Pure Lung Cancer Organoids Limit Their Utility for Personalized Medicine

Dijkstra, Krijn K.; Monkhorst, Kim; Schipper, Luuk J.; Hartemink, Koen J.; Smit, Egbert F.; Kaing, Sovann; Groot, R de; Wolkers, Monika C.; Clevers, Hans; Cuppen, Edwin; Voest, Emile E.

doi:10.1016/j.celrep.2020.107588

Cited by 158 publications

(168 citation statements)

References 32 publications

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“…35,36 Recently, Dijkstra et al established over 70 lung cancer organoids but only 17% of them were pure tumor organoids, and most of the organoids presented features of normal airway organoids. 19 Interestingly, our study showed that tumor cell purity of the PDOs had a high concordance with those in the original tissues, indicating that the accuracy of sampling could be critical for the success of organoid establishment. Moreover, we analyzed the association between tumor cell purity of the PDOs and corresponding VAFs and confirmed a significant linear relationship between tumor cell purity and VAF.…”

Section: Discussionmentioning

confidence: 70%

“…However, it is impossible to distinguish between tumor organoids and normal airway organoids based on histomorphological features only. 19 Therefore, we performed IHC staining to analyze the molecular characteristics of PDOs. IHC features of PDOs derived from ADCs and SCCs were highly concordant with those of their primary tumors.…”

Section: Establishment Of Pdo Models For Nsclcmentioning

confidence: 99%

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Genomic characteristics and drug screening among organoids derived from non‐small cell lung cancer patients

et al. 2020

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Background: Patient-derived organoid (PDO) models are highly valuable and have potentially widespread clinical applications. However, limited information is available regarding organoid models of non-small cell lung cancer (NSCLC). This study aimed to characterize the consistency between primary tumors in NSCLC and PDOs and to explore the applications of PDOs as preclinical models to understand and predict treatment response during lung cancer. Methods: Fresh tumor samples were harvested for organoid culture. Primary tumor samples and PDOs were analyzed via whole-exome sequencing. Paired samples were subjected to immunohistochemical analysis. There were 26 antineoplastic drugs tested in the PDOs. Cell viability was assessed using the Cell Titer Glo assay 7-10 days after drug treatment. A heatmap of log-transformed values of the half-maximal inhibitory concentrations was generated on the basis of drug responses of PDOs through nonlinear regression (curve fit). A total of 12 patients (stages I-III) were enrolled, and 7 paired surgical tumors and PDOs were analyzed. Results: PDOs retained the histological and genetic characteristics of the primary tumors. The concordance between tumors and PDOs in mutations in the top 20 NSCLC-related genes was >80% in five patients. Sample purity was significantly and positively associated with variant allele frequency (Pearson r = 0.82, P = 0.0005) and chromosome stability. The in vitro response to drug screening with PDOs revealed high correlation with the mutation profiles in the primary tumors. Conclusions: PDOs are highly credible models for detecting NSCLC and for prospective prediction of the treatment response for personalized precision medicine. Key points: Lung cancer organoid models could save precious time of drug testing on patients, and accurately select anticancer drugs according to the drug

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Section: Discussionmentioning

confidence: 70%

Section: Establishment Of Pdo Models For Nsclcmentioning

confidence: 99%

Genomic characteristics and drug screening among organoids derived from non‐small cell lung cancer patients

et al. 2020

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“…Our current culture success rate is 16% (or 10% if only considering organoids confidently classified as NEC), which is too low for clinical implementation at the level of individual patients. This establishment rate is lower than for CRC biopsies (71%) (34) but in the same range as for non-small lung cell cancer (35,36) or advanced prostate cancer (37). Higher success rates may be achieved by optimizing the culture medium formulation, which may differ depending on the tissue of origin.…”

Section: Discussionmentioning

confidence: 90%

Patient-Derived Organoid Models of Human Neuroendocrine Carcinoma

et al. 2021

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Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a poorly understood disease with limited treatment options. A better understanding of this disease would greatly benefit from the availability of representative preclinical models. Here, we present the potential of tumor organoids, three-dimensional cultures of tumor cells, to model GEP-NEC. We established three GEP-NEC organoid lines, originating from the stomach and colon, and characterized them using DNA sequencing and immunohistochemistry. Organoids largely resembled the original tumor in expression of synaptophysin, chromogranin and Ki-67. Models derived from tumors containing both neuroendocrine and non-neuroendocrine components were at risk of overgrowth by non-neuroendocrine tumor cells. Organoids were derived from patients treated with cisplatin and everolimus and for the three patients studied, organoid chemosensitivity paralleled clinical response. We demonstrate the feasibility of establishing NEC organoid lines and their potential applications. Organoid culture has the potential to greatly extend the repertoire of preclinical models for GEP-NEC, supporting drug development for this difficult-to-treat tumor type.

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“…17,35,36 While the success rates of establishing cultures from pleural effusion are reportedly higher, 4, 13 their use is limited as only around a tenth of all of NSCLC patients present with malignant pleural effusions. 37 Other preclinical models such as tumor organoids or xenografts also have suboptimal success rates of 20-70% or 30-40%, respectively, 11,15,16,38,39 but these have an additional issue of long establishment times of one to three months for organoids or two to ten months for xenografts. 4,11,15,16,38 Prolonged ex vivo propagation in artificial conditions may cause a functional drift of cancer cells from their original identity, and also the patient's tumor may evolve during this time, further compromising the compatibility of preclinical cultures with the diagnostic clinical decision-making process.…”

Section: Discussionmentioning

confidence: 99%

Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments

Talwelkar

Mäyränpää

Søraas³

et al. 2020

Preprint

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SUMMARYFunctional profiling of a cancer patient’s tumor cells holds potential to tailor personalized cancer treatment. Here we report the utility of Fresh Uncultured Tumor-derived EpCAM+ epithelial Cells (FUTC) for ex vivo drug response interrogation. Analysis of murine Kras mutant FUTCs demonstrated pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. Applying FUTC profiling on non-small cell lung cancer patient samples, we generated robust drug response data in 18 of 19 cases, where the cells exhibited targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling was used to guide compassionate treatment. FUTC profiling identified selective sensitivity to disulfiram and the combination of carboplatin plus etoposide and the patient received substantial clinical benefit from the treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.

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Challenges in Establishing Pure Lung Cancer Organoids Limit Their Utility for Personalized Medicine

Abstract: Highlights d Frequent overgrowth of lung cancer organoids by normal airway organoids d Copy number profiling and IHC can be used to distinguish tumor and normal organoids d Low establishment rate of pure lung cancer organoids limits their clinical utility

Cited by 158 publications

References 32 publications

Genomic characteristics and drug screening among organoids derived from non‐small cell lung cancer patients

Genomic characteristics and drug screening among organoids derived from non‐small cell lung cancer patients

Patient-Derived Organoid Models of Human Neuroendocrine Carcinoma

Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments

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