Abstract
Metastatic cells were remniscient of earlier developmental stages than primary tumor cells.
Major Finding: Metastatic cells were remniscient of earlier developmental stages than primary tumor cells.
Mechanism: High SOX9 expression in metastatic cells induced MHC class I self markers, allowing NK-cell evasion.
Impact: Knowing how developmental plasticity and metastasis interact may help find metastasis contributors.
The developmental processes that drive tissue regeneration in normal cells—for example, interconversion of epithelial cell types upon lung injury—may be co-opted in cancer cells. However, the way such developmental plasticity may be involved in metastasis and its interplay with selective pressures exerted by the immune system has not been well established. Using single-cell RNA sequencing, Laughney and colleagues characterized the transcriptional landscape of human primary and metastatic lung adenocarcinomas relative to non–tumor involved lung tissue. Their analyses revealed that the primary lung adenocarcinomas exhibited elevated levels of cells with transcriptional profiles characteristic of multiple regenerative cell types that are generally associated with response to lung injury. Uniquely, cells from metastases specifically had increased levels of SOX2 and SOX9 (encoding transcription factors that promote lung-cell specification) and transcriptionally mimicked cell types involved in endoderm and lung morphogenesis that are found upstream of the cell types transcriptionally recapitulated by primary lung tumor cells. In vivo experiments using a mouse model of lung cancer that infrequently metastasizes corroborated these findings, showing that the developmental continuum observed between primary and metastatic lung cancer cells matched the stepwise process by which primary tumor cells in the mouse model progressed to spontaneously metastasize. Mechanistically, one possible contributor to metastatic capability among the late-stage primary lung cancer cells is the development of high SOX9 expression relative to SOX2 expression. Highly SOX9-expressing cells were capable of evading clearance by natural killer (NK) cells via induction of MHC class I self markers, whereas cells highly expressing SOX2 were subject to NK cell–mediated clearance, a finding confirmed in vivo. In summary, these results illuminate previously murky details about the role of developmental plasticity in metastasis and immune evasion, and further mechanistic studies based on this work may reveal targetable vulnerabilities in cells progressing toward metastatic phenotypes.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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