[HTML][HTML] The rare YAP1 subtype of SCLC revisited in a biobank of 39 circulating tumor cell patient derived explant models: a brief report
SM Pearsall, S Humphrey, M Revill, D Morgan… - Journal of Thoracic …, 2020 - Elsevier
Journal of Thoracic Oncology, 2020•Elsevier
Introduction Recent consensus defines four SCLC subtypes on the basis of transcription
factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is
associated with “neuroendocrine (NE)-low” cells among SCLC cell lines and patient
samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor
cell–derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell
phenotype, and intertumor and intratumor heterogeneity. Methods YAP1 transcript and …
factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is
associated with “neuroendocrine (NE)-low” cells among SCLC cell lines and patient
samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor
cell–derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell
phenotype, and intertumor and intratumor heterogeneity. Methods YAP1 transcript and …
Introduction
Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with “neuroendocrine (NE)-low” cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell–derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity.
Methods
YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL.
Results
RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells.
Conclusions
YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.
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