miRNA Profiling May Unlock SCLC Biomarkers

Super-enhancer-related microRNAs (miRNAs) play a critical role in the diversity of small cell lung cancer (SCLC) and may prove to be important diagnostic and prognostic biomarkers, according to a new report. The study was published in The Journal of Pathology.¹

The molecular characteristics of SCLC have remained opaque, in part due to the cancer type’s rarity and in part because most patients diagnosed with the disease have a poor prognosis, and thus only a fraction of patients undergo surgical resection.

The use of miRNA in situ hybridization shows clear subtype-specific miRNAs, which the authors said warrant further investigation. | Image credit: CrazyJuke - stock.adobe.com

Still, recent research has suggested that frequent inactivation of TP53 and RB1 are drivers of SCLC, alongside NOTCH signaling activation.² Additional research has helped to identify 4 distinct molecular subtypes of SCLC based on the expression patterns of transcription regulators. Those subtypes include achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1).¹

Those subtypes have important implications for patients’ treatment and prognosis. For instance, the ASCL1 subtype responds to BCL2 inhibitors, while the NEUROD1 subtype appears to be sensitive to aurora kinase inhibitors.

“Prognosis also varies by subtype: the ASCL1 and NEUROD1 subtypes are generally associated with better outcomes, while the POU2F3 subtype tends to have an intermediate prognosis,” they wrote.

miRNAs are important in cancer because they play a role in several cellular processes and can have both tumor-suppressive and oncogenic roles, the authors noted. However, it is not yet clear what role miRNAs play in specific subtypes of SCLC.

With the goal of better understanding how expression patterns of subtype-specific miRNAs affect immune profiles in the SCLC tumor microenvironment, the researchers collected formalin-fixed paraffin-embedded samples from 48 patients with SCLC who underwent surgical procedures at a Japanese academic medical center between 2001 and 2021. Two of the samples could not be used in the analysis, leaving 46 samples for investigation. The authors performed miRNA visualization on the remaining 46 samples through in situ hybridization. They found high expression of miR-375 in 3 subtypes: ASCL1, NEUROD1, and ASCL1/NEUROD1. They found high expression of miR-9-5p in the POU2F3 subtype.

“Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner,” the investigators said.

Imaging mass cytometry showed that, compared to the miR-9-5p-low subtype, the miR-9-5p-high subtype of SCLC had a higher stromal area ratio, higher numbers of CD8+ T cells and CD163- macrophages in the intratumoral area, and an increased number of plasma cells in the stromal area.

The authors also said that patients with miR-375-high disease tended to have YAP1 downregulation. Those patients also had increased serum pro-gastrin-releasing peptide levels and a poor prognosis, the authors said.

The findings could have important implications for scientists’ understanding of SCLC, but they also noted several limitations to their findings. Among them, they said the small sample size and single-center design of their study could mean that the findings are not representative of the wider SCLC population. They added that their samples were obtained from surgically resected tumors and thus do not reflect any changes that might be induced by therapy. They also said none of the patients in the trial had received immune checkpoint inhibitors.

Still, they said their use of miRNA in situ hybridization shows clear subtype-specific miRNAs, which they said warrant further investigation.

“Our findings indicate that subtype-specific miRNAs have potential as novel diagnostic and prognostic biomarkers and may also serve as therapeutic targets in SCLC,” they concluded.

References

1. Horie M, Takumida H, Koba H, et al. Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer. J Pathol. Published online August 22, 2025. doi:10.1002/path.6458

2. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. doi:10.1038/nature14664