Implementing cell-free DNA of pancreatic cancer patient–derived organoids for personalized oncology

Dantes, Zahra; Yen, Hsi-Yu; Pfarr, Nicole; Winter, Christof; Steiger, Katja; Muckenhuber, Alexander; Hennig, Alexander; Lange, Sebastian; Engleitner, Thomas; Öllinger, Rupert; Maresch, Roman; Orben, Felix; Heid, Irina; Kaissis, Georgios; Shi, Kuangyu; Topping, Geoffrey J.; Stögbauer, Fabian; Wirth, Matthias; Peschke, Katja; Papargyriou, Aristeidis; Rezaee-Oghazi, Massoud; Feldmann, Katharina; Schäfer, A; Ranjan, Raphela A.; Lubeseder‐Martellato, Clara; Stange, Daniel E.; Welsch, Thilo; Martignoni, Marc E.; Ceyhan, Güralp O.; Frieß, Helmut; Herner, Alexander; Liotta, L.; Treiber, Matthias; Figura, Guido von; Abdelhafez, Mohamed; Klare, Peter; Schlag, Christoph; Algül, Hana; Siveke, Jens T.; Braren, Rickmer; Weirich, Gregor; Weichert, Wilko; Saur, Dieter; Rad, Roland; Schmid, Roland M.; Schneider, Günter; Reichert, Maximilian

doi:10.1172/jci.insight.137809

Cited by 34 publications

(33 citation statements)

References 34 publications

(48 reference statements)

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“…This observation was recently confirmed in a larger cohort [ 20 , 125 ]. More recently, similar observations were published using PDAC organoids as models [ 55 , 126 ], indicating that the transcriptome may be used to discriminate sensitive and resistant patients. This is a very important concept, since performing chemograms for each patient requires a substantial amount of material and a long time for amplification, whereas a smaller amount of material is needed for whole transcriptomic analysis.…”

Section: Chemogramssupporting

confidence: 58%

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Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer

Iovanna

2021

Translational Oncology

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Highlights A major obstacle for the effective treatment of PDAC is its molecular heterogeneity. Stratification of PDAC using markers highly specific, reproducible, sensitive, easily measurable and inexpensive is necessary. At the early stages, clinician’s priority lies in rapid diagnosis, so that the patient receives surgery without delay. At advanced disease stages, priority is to determine the tumor subtype and select a suitable effective treatment.

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Section: Chemogramssupporting

confidence: 58%

“…Therefore, to diagnose patients at early stages of disease, methods to detect ctDNA need to improve. A recent study was able to detect mutations in cfDNA from conditioned media from PDAC organoids [55] , which opens new possibilities for the use of cfDNA as a diagnostic marker.…”

Section: Liquid Biopsiesmentioning

confidence: 99%

Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer

Iovanna

2021

Translational Oncology

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“…PDO‐42 was generated from endoscopic ultrasound‐guided fine needle aspirations (EUS‐FNAs), and PDO‐48 was generated from surgical resection. The isolation process of PDOs was mostly resembling what has been described previously (Ruess et al, 2018; Renz et al, 2018a; Renz et al, 2018b; Biederstadt et al, 2020; Dantes et al, 2020). Similar to spheroid cultures from cell lines, we observed an additive to synergistic effect on cellular toxicity in single and combinatorially treated organoids (Fig 7A).…”

Section: Resultsmentioning

confidence: 74%

“…Based on the mutational profile, PDO‐48 and PDO‐42 are tumor‐derived. The step‐by‐step procedure of PDO generation and single cell dissociation for further drug testing has been described (Dantes et al, 2020). In brief, resection specimens were dissected into small fragments and washed with washing media (Advanced DMEM/F12 with 1× GlutaMax, 10 mM HEPES, and 100 μg/ml Primocin).…”

Section: Methodsmentioning

confidence: 99%

“…Next, the primary cells were mixed with Matrigel and plated as domes of Matrigel in a 24‐well plate. After solidification of the Matrigel dome, cells were supplemented with warm organoid feeding media (Boj et al, 2015; Dantes et al, 2020). For further drug testing, PDOs were dissociated into single cells as recently described (Biederstadt et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

et al. 2021

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By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

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Tumor organoids: synergistic applications, current challenges, and future prospects in cancer therapy

Kalyani

Liu

et al. 2021

Cancer Communications

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Patient-derived cancer cells (PDCs) and patient-derived xenografts (PDXs) are often used as tumor models, but have many shortcomings. PDCs not only lack diversity in terms of cell type, spatial organization, and microenvironment but also have adverse effects in stem cell cultures, whereas PDX are expensive with a low transplantation success rate and require a long culture time. In recent years, advances in three-dimensional (3D) organoid culture technology have led to the development of novel physiological systems that model the tissues of origin more precisely than traditional culture methods. Patient-derived cancer organoids bridge the conventional gaps in PDC and PDX models and closely reflect the pathophysiological features of natural tumorigenesis and metastasis, and have led to new patient-specific drug screening techniques, development of individualized treatment regimens, and discovery of prognostic biomarkers and mechanisms of resistance. Synergistic combinations of cancer organoids with other technologies, for example, organ-on-a-chip, 3D bio-printing, and CRISPR-Cas9-mediated homology-independent organoid transgenesis, and with

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Implementing cell-free DNA of pancreatic cancer patient–derived organoids for personalized oncology

Cited by 34 publications

References 34 publications

Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer

Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

Tumor organoids: synergistic applications, current challenges, and future prospects in cancer therapy

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