Driven by advances in scientific understanding, the treatment of non-small cell lung cancer (NSCLC) has begun to see successes one subtype at a time.

At the 2021 World Conference on Lung Cancer (WCLC), which is currently being held in virtual format, resear chers were optimistic that the same path would be possible for small-cell lung cancer (SCLC).

"Our approach to small-cell overall, I think, is going to be blown wide open in the next 10 years, because of the work being done overall in molecular subtyping and understanding at an earlier stage" Anne Chiang, medical oncologist at Yale University School of Medicine, told the audience at an oral abstract session titled "What's on the horizon for SCLC?"

It is an indication that could use any progress. SCLC metastasizes early, and while it is initially responsive to first-line chemotherapy, it "recurs with a vengeance," Christine Lovly, associate professor of medicine at Vanderbilt University, told the audience at the session.

As a result, two-thirds of patients are diagnosed after the tumor has metastasized, and for this group, the 5-year survival rate is under 1%.

Adding immunotherapy to front-line chemotherapy has improved outcomes slightly, but that success has been tempered by a string of clinical failures. The newest such failure was presented at WCLC's opening presidential plenary, where it was reported that, compared to the standard-of-care chemotherapy, combination treatment with lurbinectedin and doxorubicin failed to have any impact whatsoever on the overall survival of trial participants with recurrent SCLC in the phase III ATLANTIS trial.

Charles Rudin, a physician-scientist at Memorial Sloan-Kettering Cancer Center (MSKCC), and his colleagues were the first to identify SCLC subtypes with distinct transcriptional signatures, driven by the transcription factors ASCL1 (A), NEUROD1 (N) and POU2F3 (P), respectively, as well as an inflamed subtype.

However, "unanswered questions include whether these subtypes have different metastatic potential or immune microenvironments, whether there is plasticity between subtypes, and whether anomalous small-cell lung cancer phenotypes exist," Joseph Minhow Chan told the audience at the SCLC oral session.

Chan, a postdoctoral fellow at MSKCC and mentee of Rudin's as well as of Dana Pe'er, described the use of single-cell sequencing to look for answers to those questions.

Single-cell specifics

In their work, the team looked at almost 55,000 cells from 21 SCLC tumor samples derived both from biopsies of primary tumors and from metastases.

Only one of those tumors was a subtype P, so Chan and his colleagues focused their analysis on A- and N-type tumors. They showed that A-type transcriptional signatures were more frequent in primary lung samples, while N and P were enriched in lymph nodes and distant metastases.

The team also showed that subtype N samples more strongly expressed genes related to epithelial-mesenchymal transition (EMT), as well as several genes that led to similarities with neurons. The N subtype also had decreased numbers of immune cells, and T cells that were dysfunctional compared with those in the other subtypes.

The investigators also identified what Chan called "a stem-like prometastatic phenotype" that cut across the known A, N and P subtypes.

The characteristic feature of that subtype was high levels of the enzyme phospholipase gamma (PLGC2), which has functions related to cell motility. Such tumors also had high levels of profibrotic cells.

In both cell and animal experiments, overexpression of PLGC2 increased metastasis, and in clinical samples the team looked at, high PLGC2 levels were correlated with shorter survival times.

In another presentation at the session, Yujuan Jin, a researcher at the Shanghai Institute of Biological Sciences, described her team's work on epigenetic factors contributing to metastasis.

Jin and co-authors identified a marker that consisted of high expression of the cell adhesion molecule NCAM and low expression of the cell surface marker CD44 that was characteristic of metastasizing cells.

"Mechanistically," the authors wrote in their abstract, those cells emerged when "TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by the SWI/SNF complex. Down-regulation of TAZ promotes the transition from Non-SMC to SMC and facilitates SCLC metastasis. Conversely, ectopic TAZ expression or TAZ activation by digitoxin treatment reversibly promotes the transition from SMC to Non-SMC and thus alleviates SCLC metastasis."

In discussing the abstracts, Anne Chiang, associate professor of medicine at Yale University School of Medicine, said that the ongoing research is allowing a more nuanced understanding of SCLC as a tumor that can have different cell types of origin and genetic drivers, rather than "a monolithic entity."

The data, she added, were "still early for clinical therapeutic impact. But I have no doubt that it's going to lead to that."