A spatial multi-omics study of the rare lung cancer subtype known as combined small-cell lung cancer (cSCLC) has shown that these mixed tumors, which contain features of both small-cell and non-small-cell lung cancer (NSCLC), arise from a single ancestral cell that evolves and transitions between the two cancer types over time.
The results “provide a foundation for understanding cSCLC evolution and advancing innovative diagnostics and therapeutics,” write the authors in Cell Reports Medicine.
cSCLC represents approximately 2–5% of all SCLC cases, with diagnosis primarily based on pathologic evaluation of surgically resected tumor specimens. This can lead to underdiagnosis because small biopsies may not capture the full histological diversity of the tumor. Although cSCLC is more diverse and has a worse prognosis than typical SCLC, it is usually treated the same way because its underlying biology and tumor environment are not well understood.
Traditionally, the mixed histologies within cSCLC were thought to arise from independent tumor populations, but recent studies have revealed that the different histological components share common genetic mutations.
To investigate further, Zhuo Wang, from Fudan University in Shanghai, China, and colleagues applied spatially resolved genomic and transcriptomic sequencing, alongside single-cell RNA sequencing, to 19 treatment-naive cSCLC tumors.
“We found that these tumors are not simply mixtures of different cancer types,” said Wei Wei, PhD, associate professor at the Institute for Systems Biology in Seattle and co-corresponding author of the study. “They are dynamic systems, with cancer cells actively changing their identity. That flexibility may help explain why they are so difficult to treat.”
The team reports that the different tumor components originate from a single clone but later diverge as they acquire different mutations and copy-number changes.
The study also revealed that tumor cells can exist in intermediate or hybrid states, carrying features of multiple cancer types at once. About one-third of the SCLC-like tumor cells analyzed showed these mixed identities, suggesting that cancer progression is not a simple on-off switch, but a continuum.
In addition, the researchers found that different regions within the same tumor create distinct microenvironments. Some areas were rich in immune cells, while others were largely immune-excluded. Dense bands of fibroblasts often separated these regions. Those fibroblast-rich boundaries may help wall off parts of the tumor from immune attack.
“By combining spatial genomics, single-cell analysis, and multi-region sequencing, we were able to trace how these tumors evolve across both space and time,” said Fudan University’s Qihui Shi, PhD, co-corresponding author of the study. “This approach allowed us to capture transitional cell states that are not visible using conventional methods.”
Finally, the researchers developed “cSCLC Detector,” a four-gene diagnostic tool that may help identify these mixed tumors more accurately. The tool was built on a key insight from the study: although the small-cell and non-small-cell parts of cSCLC can look very different under the microscope, they come from the same ancestral tumor and share early trunk mutations.
In independent biopsy and blood samples, the assay, which detects mutations in the NSCLC-specific driver genes EGFR, KRAS, BRAF, and PIK3CA, identified cSCLC-like cases in 14% of samples, compared with a prevalence of 2%–5% estimated from surgically resected specimens.
The findings highlight the importance of understanding not just the genetic mutations in cancer, but also how cancer cells change state and interact with their environment.
“Cancer is not static,” Wei said. “To treat it effectively, we need to understand how it evolves—not just what it is at a single point in time.”
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