Lung Metastases in Pancreatic Cancer: Timing Their First Breath.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor survival rate. This is largely due to patients being diagnosed when the disease has already metastasized to other organs, most commonly the liver and lungs. For these patients, no effective treatment exists, and the 5-year survival rate is less than 5%. Despite its highly metastatic nature, the timing and mechanisms of metastasis formation in PDAC remain largely unknown. In this issue of Cancer Research, Lasse Opsahl and colleagues identify a role for premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in lung premetastatic niche formation. By performing histology and single-cell RNA sequencing analyses of a KRASG12D inducible mouse model of PDAC, the authors identify pSTAT3+ fibroblasts in the lungs, but not the liver, upon PanIN formation. Notably, pSTAT3+ fibroblasts in the lungs are required for metastasis formation. Mechanistically, KRAS activation in the pancreatic epithelium and consequential IL6 release activate STAT3 in lung fibroblasts. Altogether, Lasse Opsahl and colleagues demonstrate that PanIN lesions prime the lungs to favor future malignant cell outgrowth before the development of a pancreatic tumor and that blocking the formation of this lung premetastatic niche impairs metastasis in mice. See related article by Lasse Opsahl et al., p. 22.