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Perturb-seq experiment on patient-derived cancer-associated fibroblast in vitro cell line models from pancreatic ductal adenocarcinoma

ABSTRACT: Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their plethora of pro- and antitumorigenic functions. Recent findings attributed this functional heterogeneity to specializations in CAF subtypes. A precise targeting of specific subtypes would thus be required to design therapies that effectively modulate CAF phenotypes, but our knowledge of CAF heterogeneity in solid tumors, particularly pancreatic ductal adenocarcinoma (PDAC), is still lacking. Here, we use single-cell transcriptomics to characterize CAF subtype heterogeneity in in vitro CAF cell lines isolated from pancreatic tumor patients and investigate subtype-resolution modulations arising from perturbing potential stromal genes. We use the immortalized CAF cell lines to perform single-cell CRISPR perturbations of candidate stromal targets, revealing not only the subtype-specific effects of the perturbations, but also the impact of model-type selection on the translatability of insights.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306853 | GEO | 2025/09/12

REPOSITORIES: GEO

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Project description:Epithelial ovarian cancer is a very heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Rational therapeutic approaches need to account for interpatient and intratumoral heterogeneity in treatment design. Detailed characterization of in vitro models representing the different histological and molecular subtypes is therefore imperative. Strikingly, from ~100 available ovarian cancer cell lines the origin and which subtype they represent is largely unknown. We have extensively and uniformly characterized 39 ovarian cancer cell lines (with mRNA/microRNA expression, exon sequencing, dose response curves for clinically relevant therapeutics) and obtained all available information on the clinical features and tissue of origin of the original ovarian cancer to refine the putative histological subtypes. From 39 ovarian cell lines, 14 were assigned as high-grade serous, four serous-type, one low-grade serous and 20 non-serous type. Three morphological subtypes (21 Epithelial, 7 Round, 12 Spindle) were identified that showed distinct biological and molecular characteristics, including overexpression of cell movement and migration-associated genes for the Spindle subtype. Clinical validation showed a clear association of the spindle-like tumors with metastasis, advanced stage, suboptimal debulking and poor prognosis. In addition, the morphological subtypes associated with the molecular C1-6 subtypes identified by Tothill et al. [1], Spindle clustered with C1-stromal subtype, Round with C5-mesenchymal and Epithelial with C4 subtype. We provide a uniformly generated data resource for 39 ovarian cancer cell lines, the ovarian cancer cell line panel (OCCP). This should be the basis for selecting models to develop subtype specific treatment approaches, which is very much needed to prolong the survival of ovarian cancer patients. Gene expression was measured for 32 ovarian cancer cell lines using the GeneChip Human Exon 1.0 ST Array (Affymetrix). Morphological subtypes were assigned based on cell morphology, size, growth pattern and proliferation rate during culturing of the cell lines.

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Perturb-seq experiment on patient-derived cancer-associated fibroblast in vitro cell line models from pancreatic ductal adenocarcinoma

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