Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies

Abstract

The bone marrow microenvironment modulates treatment response in blood cancers but a systematic assessment of anticancer drug effects in the context of this protective niche has been missing. To fill this gap, we established an ex-vivo model that enables high-throughput compound screening in leukemia-stroma coculture. We applied 50 compounds to 108 patient samples with hematological malignancies in monoculture and coculture with bone marrow stromal cells and measured cellular phenotypes via automated confocal microscopy. Stromal coculture conferred resistance to 52% of compounds in chronic lymphocytic leukemia (CLL) and to 36% of compounds in acute myeloid leukemia (AML). Although a partial loss in efficacy was observed for a considerable number of investigated drugs, responses to many of the drugs were comparable between mono- and cocultures. This suggests that large-scale monoculture drug perturbation studies might be sufficient for the purpose of first-line screening. However, our study also uncovered a substantial heterogeneity of stromal protection across the probed samples and compounds, which highlights the importance of validating the findings of monoculture screens in stroma coculture models.

Gas-Phase Fractionation Data-Independent Acquisition Analysis of 3D Cocultured Spheroid Tumor Model Reveals Altered Translational Processes and Signaling Using Proteomics

“…Coculture tumor models have emerged as a diverse tool to interrogate interactions between multiple cell types, such as tumor and stromal cells. Cocultures have been used as a cell model to study heterotypic cell signaling and proteomic crosstalk in pancreatic, liver, and breast cancer, and they have recently started to be used to examine processes in CRC. − Mammalian in vitro cocultures have shown decreased sensitivity to drug therapies compared to monocultures. However, most preclinical research uses monoculture models, which often fail to capture the cell heterogeneity found within in vivo tumors …”

Stromal cells engineered to express T cell factors induce robust CLL cell proliferation in vitro and in PDX co-transplantations allowing the identification of RAF inhibitors as anti-proliferative drugs

“…The lack of primary CLL cell proliferation in vitro poses challenges to studying this process, which is fundamental for understanding disease progression and aggressiveness. Several in vitro microenvironment model systems have been developed to study CLL biology, perform in vitro screening of chemical libraries for compounds with anti-CLL activity, and guide therapeutic decisions [19][20][21][22]. Most such co-culture models involve human or murine fibroblast-like stromal cells that provide signals to overcome spontaneous CLL cell apoptosis and/or mimic adhesion-mediated drug resistance, but these do not trigger proliferation [4,[22][23][24][25].…”

Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

“…Several studies have investigated individual components of the microenvironment in leukaemia (Dietrich et al , 2012 ; Chatzouli et al , 2014 ; Jayappa et al , 2017 ; Chen et al , 2019 ; preprint: Herbst et al , 2022a ). However, systematic studies, particularly those exploring cell‐extrinsic influences on drug response, are rare.…”