Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients

Ooft, Salo; Weeber, Fleur; Dijkstra, Krijn K.; McLean, Chelsea; Kaing, Sovann; Werkhoven, Erik van; Schipper, Luuk J.; Hoes, Louisa R.; Vis, Daniël J.; Haar, Joris van de; Prevoo, Warner; Snæbjörnsson, Pétur; Velden, Daphne van der; Klein, Michelle; Chalabi, Myriam; Boot, H.; Leerdam, Monique E. van; Bloemendal, Haiko J.; Beerepoot, Laurens V.; Wessels, Lodewyk F.A.; Cuppen, Edwin; Clevers, Hans; Voest, Emile E.

doi:10.1126/scitranslmed.aay2574

Cited by 549 publications

(575 citation statements)

References 32 publications

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“…We are continuing prospective patient inclusion in the observational study, and are currently planning an interventional study for clinical translation of our ex vivo pharmacogenomics platform for patients with relapse after hepatic resection and/or non-resectable CRLM. A step forward was taken last fall, when Ooft et al (47) showed that ex vivo drug screen of PDOs correctly predicted response of irinotecan-based chemotherapy in patients with metastatic CRC.…”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Bruun

Kryeziu

Eide

et al. 2020

Clinical Cancer Research

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Translational relevance The majority of PDOs from colorectal liver metastases were sensitive to anticancer drugs in clinical use and/or under development in late-phase clinical trials. Together with only a modest level of intrapatient inter-metastatic pharmacological heterogeneity, this reinforces a potential benefit from off-label use of drugs guided by both pharmacological profiling and established molecular markers. Correlation in the overall variation at the drug sensitivity and gene expression levels supports the relevance of transcriptomic profiling in pharmacogenomic assessments. Research.

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Section: Discussionmentioning

confidence: 99%

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Bruun

Kryeziu

Eide

et al. 2020

Clinical Cancer Research

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show abstract

“…Presently, despite continually expanding cancer treatment options, it remains difficult to predict which tumors might respond to which treatments [42,43]. Our data underscore the need to uncover genetic weaknesses that might render tumors derived from the same tissue differentially responsive to particular therapies and reveal mechanisms that tumors might utilize for drug evasion.…”

Section: Discussionmentioning

confidence: 96%

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift

et al. 2020

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The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. Here, we demonstrate that hypoxia augments the capacity of melanoma cells to withstand cisplatin and doxorubicin cytotoxicity. We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate human‐relevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin. The differences are manifested in magnitude of proliferative arrest and cell death rates, extent of mtDNA depletion, and impairment of mitochondrial respiration. In both models, cytotoxicity is mitigated by hypoxia, which augments glycolytic metabolism. Collectively, the findings implicate metabolic reprogramming in drug evasion and suggest that melanoma tumors with distinct genetic makeup may have differential drug vulnerabilities, highlighting the importance of precision anticancer treatments.

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“…Using functional enrichment, many cancer-associated functions, such as MAPK cascade, Ras signaling pathway, PI3K-Akt signaling pathway, positive regulation of cell migration and positive regulation of cell proliferation, were identified (Table S7). With the accumulation of published studies about CRC organoids and multidimensional omics data of organoids (Fumagalli et al, 2017;Newey et al, 2019;Ooft et al, 2019), our method could be used to identify more extensive gene paths and construct the landscape of molecular pathogenesis for CRC cancer. Sequential introduction of the mutations in gene paths may provide a new avenue for understanding the dynamic progression of CRC.…”

Section: Discussionmentioning

confidence: 99%

Prioritizing Gene Cascading Paths to Model Colorectal Cancer Through Engineered Organoids

Ping

et al. 2020

Front. Bioeng. Biotechnol.

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Engineered organoids by sequential introduction of key mutations could help modeling the dynamic cancer progression. However, it remains difficult to determine gene paths which were sufficient to capture cancer behaviors and to broadly explain cancer mechanisms. Here, as a case study of colorectal cancer (CRC), functional and dynamic characterizations of five types of engineered organoids with different mutation combinations of five driver genes (APC, SMAD4, KRAS, TP53, and PIK3CA) showed that sequential introductions of all five driver mutations could induce enhanced activation of more hallmark signatures, tending to cancer. Comparative analysis of engineered organoids and corresponding CRC tissues revealed sequential introduction of key mutations could continually shorten the biological distance from engineered organoids to CRC tissues. Nevertheless, there still existed substantial biological gaps between the engineered organoid even with five key mutations and CRC samples. Thus, we proposed an integrative strategy to prioritize gene cascading paths for shrinking biological gaps between engineered organoids and CRC tissues. Our results not only recapitulated the well-known adenoma-carcinoma sequence model (e.g., AKST-organoid with driver mutations in APC, KRAS, SMAD4, and TP53), but also provided potential paths for delineating alternative pathogenesis underlying CRC populations (e.g., A-organoid with APC mutation). Our strategy also can be applied to both organoids with more mutations and other cancers, which can improve and innovate mechanism across cancer patients for drug design and cancer therapy.

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Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients

Cited by 549 publications

References 32 publications

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift

Prioritizing Gene Cascading Paths to Model Colorectal Cancer Through Engineered Organoids

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