A new pancreatic adenocarcinoma‐derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms

Abstract

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Uncovering the hidden threat: single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer

“…Over the past years, patient-derived tumor organoids emerged as promising cancer models for personalized medicine, since they preserve the clonal heterogeneity, mutational landscape, and histological architecture of the originating tumor tissue [9][10][11] . Furthermore, recent studies provided first evidence that tumor organoids responded similarly to the corresponding patient when treated with the same standard of care therapy.…”

Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine?

“…They further demonstrated that the combined MEK and ERBB inhibition using the MEK inhibitor selumetinib and the pan-ERBB inhibitor neratinib of human organoid orthotopic xenografts resulted in tumor regression in short-term intervention studies [ 66 ]. Another example is the investigation and comprehension of the underlying mechanism of resistance development of PDAC against FOLFIRINOX regimen, as demonstrated in a recent study by Bachir et al, with the aid of PDOs [ 67 ]. Besides the use of PDOs for drug studies, these models are already in use to uncover and validate novel targets and signaling pathways involved in pancreatic cancer progression [ 51 , 52 , 56 , 68 ].…”

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

“…Our own findings indicate that even after harsh drug combinations, individual tumor cells may survive and even regrow once the drugs are withdrawn. Cancer cells adapt and become resistant to sublethal doses of anticancer agents, as was shown for FOLFIRINOX in PDOs [100], but would it be possible to predict which cells or subclones are going to survive even before treatments are started, e.g., using lineagetracing? Further, would combining transcriptome, epigenome, proteomic and genome data, possibly at the single-cell and spatial level with advanced organoid models including necessary stromal components, really reveal the relevant mechanisms and evolution of drug resistance, or will the wealth of data rather confound efforts to develop effective solutions for pancreatic cancer patients?…”

“…We also know that tumor responses in clinical settings are transient at best. Recently, organoids were used to model adaptive resistance to FOLFIRINOX, which was associated with differential transcriptional reprogramming [100]. To establish if organoids can allow us to study how tumors escape even harsh cytotoxic chemotherapies and other treatments, we tracked individual cells in organoids over several days by confocal microscopy using a live cell nuclear labeling agent.…”