Analysis of master regulatory transcription factors and their associated transcriptomic profiles in SCLC patients

Despite extensive research small cell lung cancer (SCLC), a highly aggressive neuroendocrine tumor, is characterized by a poor clinical outcome and limited response to conventional chemotherapy. Gene expression analyses have recently defined subgroups of SCLC and helped to understand intertumoral heterogeneity and plasticity. In particular the master regulatory transcription factors of neuroendocrine differentiation ASCL1, NEUROD1 and POU2F3 show differential expression in SCLC cohorts. Preclinical models demonstrate that variations in the activity of these TF are associated with significant differences regarding morphology and biology, including response to therapy.

Resection specimen from 30 patients with SCLC as defined by standard morphological and immunohistochemical criteria were retrieved from the archive and tissue microarrays (TMA) constructed. All cases were classified based on the immunohistochemical expression of the dominant master regulatory transcription factors, namely NEUROD1-predominant, ASCL1-predominant, NEUROD1-ASCL1-hybrid, POU2F3-predominant, and negative (Null) phenotypes. Using the GeoMx Digital Spatial Profiler (DSP) platform, we performed transcriptomic analysis on 15,359 mRNA transcripts in multiple TMA tumor spots from each SCLC case.

The SCLC tumors could be subclassified by IHC into 4 NEUROD1-predominant, 8 ASCL1- predominant, 4 NEUROD1-ASCL1-hybrid, 8 POU2F3-predominant, and 6 negative (Null) phenotypes. The transcriptomic analysis revealed unique transcriptomic signatures of the different phenotypes. 172 unique transcripts were identified for POU2F3- , 48 unique transcripts for the ASCL1-NEUROD1-hybrid, and 92 unique transcripts for the Null phenotypes. In contrast, common transcriptomic signatures were measured in ASCL1- and NEUROD1-predominant phenotypes that showed distinct overlap with Null and ASCL1-NEUROD1-hybrid phenotypes for 13 mRNA transcripts.

SCLC subgroups as defined by IHC of the neuroendocrine master regulators show specific transcriptomic signatures. Using these signatures SCLC biology can be better elucidated and new targets for therapy defined.

Publication History

Article published online:
18 March 2025