The critical role of cellular polarity and inflammation in facilitating the spread of cancerous clusters through the lungs is described in a new study examining the mechanisms underpinning “spread through air spaces” (STAS), a key factor in the prognosis of lung cancers and pulmonary metastases.

First defined in the 2015 WHO classification of lung tumors, STAS describes the presence of tumor cells floating within the air spaces of the lung parenchyma beyond the primary tumor. STAS is associated with poor outcomes in lung adenocarcinomas and pulmonary metastases of colorectal cancer (CRC), often predicting high rates of local recurrence even after complete surgical resection. Despite its prognostic importance, the biological mechanisms driving STAS have remained elusive.

The study, published in The Journal of Pathology, highlighted a phenomenon known as polarity switching in cancer cell clusters. Under normal conditions, epithelial cells exhibit apico-basal polarity, with their “apical” surface facing outward. However, in STAS, researchers observed tumor cell clusters adopting an “apical-out” polarity, particularly when detached and floating in air spaces.

Using organoid models derived from colorectal cancer and lung cancer, the researchers demonstrated that apical-out clusters had significantly greater metastatic capacity than single cells. When introduced into mouse lungs, these clusters formed metastases efficiently, transitioning to “apical-in” polarity upon establishing attachment at new sites.

Interestingly, the airway epithelium itself appeared to resist adhesion by STAS clusters. However, this protective barrier was overcome when exposed to the inflammatory cytokine transforming growth factor-beta 1 (TGF-β1). TGF-β1 pre-treatment altered the airway epithelium, increasing its susceptibility to adhesion by STAS clusters.

The study identified follistatin-like protein 1 (FSTL1) as a crucial mediator in this process. TGF-β1 stimulation induced the expression of FSTL1 in airway epithelial cells. FSTL1 promoted the loss of apical polarity in cancer clusters, enabling them to adhere more effectively to the airway epithelium. This adhesion was further linked to activation of SRC family kinases (SFKs), which play a role in cellular polarity remodeling.

“Adhesion was suppressed by a compound or proteins that blocked the polarity change, and organoids from micropapillary carcinomas in a stable apical-out state had low adhesion rates,” wrote lead author Yoshiaki Matsuura, from the Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

By establishing an in vitro model of STAS, the researchers demonstrated how inflammation and polarity dynamics drive the spread of cancer clusters in the lungs. These findings could lead to new approaches for treating lung cancers and pulmonary metastases. The authors suggest approaches including targeting polarity switching via use of inhibitors of polarity remodeling, such as dasatinib, in order to reduce the metastatic potential of STAS clusters by preserving their apical-out configuration and preventing adhesion. Therapies aimed at reducing TGF-β1 signaling or its downstream effectors, like FSTL1, may enhance the lung’s natural defenses against cancer spread. Additionally, the authors note that understanding STAS dynamics may improve surgical strategies, particularly in deciding the extent of resection to minimize recurrence risks.

While this study advances our understanding of STAS, questions remain about the genetic and environmental factors influencing polarity switching and inflammation. Additional research is needed to explore how these findings translate across different cancer types and patient populations.

The authors’ conflict of interest statement is included in the study.