Introduction/Background ARK1-USC, a highly annotated USC-derived cell line with a clinically relevant mutation spectrum,1 is employed in vitro and in vivo for translational studies of novel USC therapies.2 In ovarian cancer, stemness and malignancy-supporting collagen microenvironment coincide. Both promote resistance to therapy. Considering the shared histological and molecular characteristics of USC and OSC, we hypothesized that USC cells likewise display ovarian markers for stemness and collagen regulators of stemness. We tested this prediction in ARK1-USC.
Methodology Profiling of the time-dependent transcriptome, with flow cytometric analysis of select protein markers.
Results ARK1-USC expressed the repertoire of cancer stem cell (CSC) markers of ovarian malignancies, such as CD44, CD117, CD144, CD133, ROR1, and ALDH1A1. Relative to 12 h after plating, at 48 h expression was decreased (CD117 and ROR1 by half, FDR adjusted p-value [q] ≤ 0.003); increased (ALDH1A1 and CD144 2.5- and 2.1-fold (q=0.027 and q≤0.000, resp.); or unchanged (CD44 and CD133). ARK1-USC also expressed i) the stemness-maintaining COL18, shown in OSC3; and ii) the malignant microenvironment collagen types VI and XI, COL6A1/COL6A2/COL6A3 and COL11A1/COL11A2, shown in OSC to cause platinum resistance4 and poor prognosis.5 Using fluorophore-labelled monospecific antibodies, flow cytometry confirmed collagen type VI and XVIII production by ALDH1A1 expressing ARK1-USC. In contradistinction to ovarian cancer, ARK1-USC expressed the CSC marker nerve growth factor receptor (NGFR), increasing 3-fold by 48 h (q=0.039); nerve growth factor (NGF) was not expressed at any time. Nevertheless, multiple genes regulating neurogenesis, synaptic plasticity and excitation, axonal transport, and neuron epigenetic reprogramming were expressed, in addition to an inventory of neuronal receptors for neurotransmitters like acetylcholine (e.g. CHRNA3/CHRNA4/CHRNA5), dopamine/epinephrine/norepinephrine (e.g. ADRA1B/ADRA2C/ADRB1/ADRB2/DDR2/DRD4), serotonin (e.g. HTR2B, HTR6) and the enzymes required for their synthesis (e.g. TPH2, TH).
Conclusion ARK1-USC classify as CSCs with neuronoid propensity. We propose that in reaction to therapies in vivo, a cancer cell subpopulation stabilized in its proper niche of malignant matrix can temporarily differentiate into neuron-like non-proliferative cells endowed with enhanced chemo- and radiation-resistance. This conceptual framework, which captures the current clinical experience with USC treatment, is worthy of further study as it envisions a previously unnoted cytological sanctuary that still holds promising novel mechanistic targets for interdicting cancer cell entry and persistence.
Disclosures The authors have nothing to disclose.
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