In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening

Our plain-English summary of In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening, by A.R. Mazzocchi, S.A.P. Rajan, K.I. Votanopoulos, et al (Scientific Reports, 2018).

The study

• Authors: A.R. Mazzocchi, S.A.P. Rajan, K.I. Votanopoulos, A.R. Hall, A. Skardal
• Journal: Scientific Reports
• Published: 2018;8(1):2886
• Cited by: 125 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Variability in patient response to anti-cancer drugs is currently addressed by relating genetic mutations to chemotherapy through precision medicine. However, practical benefits of precision medicine to therapy design are less clear. Even after identification of mutations, oncologists are often left with several drug options, and for some patients there is no definitive treatment solution. There is a need for model systems to help predict personalized responses to chemotherapeutics. We have microengineered 3D tumor organoids directly from fresh tumor biopsies to provide patient-specific models with which treatment optimization can be performed before initiation of therapy. We demonstrate the initial implementation of this platform using tumor biospecimens surgically removed from two mesothelioma patients. First, we show the ability to biofabricate and maintain viable 3D tumor constructs within a tumor-on-a-chip microfluidic device. Second, we demonstrate that results of on-chip chemotherapy screening mimic those observed in subjects themselves. Finally, we demonstrate mutation-specific drug testing by considering the results of precision medicine genetic screening and confirming the effectiveness of the non-standard compound 3-deazaneplanocin A for an identified mutation. This patient-derived tumor organoid strategy is adaptable to a wide variety of cancers and may provide a framework with which to improve efforts in precision medicine oncology.

In plain English

This was a laboratory study, not a study of asbestos exposure. The authors grew three-dimensional tumor models ("organoids") on a fluid-fed chip. The tumor tissue came from surgery on two patients at Wake Forest Baptist Medical Center: a 50-year-old man with epithelioid malignant peritoneal mesothelioma, and a 38-year-old woman whose tumor was finally classified as well-differentiated papillary-cystic mesothelioma. Most cells were alive at the first check (93.3% and 84.5%), and the organoids carried mesothelioma markers. In subject 1's organoids, cisplatin/pemetrexed lowered live cells to 39.0% at the low dose and 11.8% at the high dose, against 52.1% and 39.8% for carboplatin/pemetrexed. Subject 2's organoids responded less to cisplatin/pemetrexed (62.2% and 62.5%) than to carboplatin/pemetrexed (54.5% and 43.7%). The authors reported that these patterns matched each patient's response to cisplatin-based treatment. The experimental drug DZNep was tested because subject 1's tumor had a BAP1 mutation. It significantly reduced cell metabolism in subject 1's organoids, but not in subject 2's or in a colorectal cancer cell line. The authors noted that only two patients were studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study using 3D tumor organoids grown from patient tumor cells in a microfluidic device, with drug screening; no animals were used
• Who was studied: Tumor tissue from two patients with peritoneal mesothelioma, removed during surgery at Wake Forest Baptist Medical Center (USA). Subject 1 was a 50-year-old male with epithelioid malignant peritoneal mesothelioma. Subject 2 was a 38-year-old female first diagnosed with epithelioid peritoneal mesothelioma, whose final pathology showed well-differentiated papillary-cystic mesothelioma. A colorectal cancer cell line (HCT116) served as a control in the DZNep experiments.
• Exposure: No asbestos or fiber exposure was studied. The exposures were drugs given to the organoids: cisplatin/pemetrexed and carboplatin/pemetrexed at 0.1 and 10 micromolar (subject 1) or stated as 0.2 and 20 micromolar (subject 2), and the experimental EZH2 inhibitor 3-deazaneplanocin A (DZNep) at 0.1, 1 and 10 micromolar for 96 hours.
• Main results:
  • At the first time point (day 7 for subject 1, day 1 for subject 2), 93.3% and 84.5% of cells, respectively, were alive in the organoids
  • Organoids from both subjects showed co-staining for mesothelioma markers (CK5/6 with calretinin and with thrombomodulin), which the authors took as retention of the mesothelioma phenotype
  • Untreated subject 1 organoids had 87% live cells after 14 days, a decrease that was not statistically significant
  • In subject 1 organoids, carboplatin/pemetrexed reduced viability to 52.1% at 0.1 micromolar and to 39.8% at 10 micromolar
  • In subject 1 organoids, cisplatin/pemetrexed reduced viability to 39.0% at 0.1 micromolar and to 11.8% at 10 micromolar. These declines were significant relative to each other (p less than 0.05) and to controls (p less than 0.05 and p less than 0.01, respectively).
  • In subject 2 organoids, cisplatin/pemetrexed reduced viability to 62.2% and 62.5% at the low and high doses, which the authors described as not a significant dose-dependent response
  • In subject 2 organoids, carboplatin/pemetrexed reduced viability to 54.5% and 43.7% at the low and high doses
  • DZNep caused a significant decrease in mitochondrial metabolism in subject 1 organoids (whose tumor had a BAP1 mutation), but no significant decrease in HCT116 colorectal cancer organoids
  • Subject 2 organoids (no actionable mutations identified) showed no decrease in metabolism with DZNep, and a less pronounced decrease in live-to-dead cell ratio than subject 1
• The authors' conclusion: The authors concluded that in vitro drug screening of patient-derived mesothelioma organoids is feasible. They stated that the organoid responses matched the subjects' responses to cisplatin-based therapy, which they said suggests patient-specific drug effectiveness may be recapitulated in their system.
• Limitations the authors state:
  • Only two subjects were studied
  • The mutation-guided drug test was only a single example
  • Only a small number of drugs was tested
  • The effectiveness of the two drug combinations could not be compared systematically within the patient
  • Platform robustness, reproducibility and take rate still need further study

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy.

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