Senolytic targeting of CAF-induced KRT17+ colon cancer cells inhibits metastatic invasion

Shiokawa, D.; Sakai, H.; Kanda, Y.; Ohata, H.; Asada, Y.; Ochiai, H.; Fukagawa, T.; Sekine, S.; Yatabe, Y.; Morikawa, M.; Nakagama, H.; Okamoto, K.

doi:10.64898/2026.03.03.708913

bioRxiv · 10.64898/2026.03.03.708913

Senolytic targeting of CAF-induced KRT17+ colon cancer cells inhibits metastatic invasion

Shiokawa, D.·Sakai, H.·Kanda, Y.·Ohata, H.·Asada, Y.·Ochiai, H.·Fukagawa, T.·Sekine, S.·Yatabe, Y.·Morikawa, M.·Nakagama, H.·Okamoto, K.

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Abstract

Metastasis remains the leading cause of cancer mortality, yet effective strategies to eliminate metastasis-initiating cells are lacking. Here, we dissected intratumoral heterogeneity in colon cancer using single-cell analyses and identified a KRT17+ slow-cycling cancer cell population that exhibits features of metastasis-initiating cells (L1CAM) and senescent-like cells (CDKN2A, BCL2L1). Spatial transcriptomics and immunostaining revealed that these cells localize at tumor-stroma interfaces, where they are closely associated with TGF-{beta}1-producing subset of cancer-associated fibroblasts (CAFs) and exhibit SMAD3 activation. Mechanistically, TGF-{beta}1 induces KRT17 expression in patient-derived cancer cells, while co-culture with CAFs drives the emergence of KRT17 migratory cells in a KRT17-dependent manner. Functionally, genetic ablation of KRT17 or senolytic targeting of BCL2L1 suppresses peritumoral invasion and liver metastasis in xenograft models. Clinically, KRT17 cells co-localize with TGF-{beta}1 CAFs, and their co-expression with L1CAM correlates with advanced disease stage. These findings support a model in which stromal TGF-{beta} signaling promotes the emergence of a KRT17 invasive cancer cell state with senescence-associated features and suggest that senolytic strategies may represent a potential approach to limit metastatic progression in colon cancer.

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Shiokawa, D., Sakai, H., Kanda, Y., Ohata, H., Asada, Y., Ochiai, H., Fukagawa, T., Sekine, S., Yatabe, Y., Morikawa, M., Nakagama, H., Okamoto, K.. 2026-03-05. Senolytic targeting of CAF-induced KRT17+ colon cancer cells inhibits metastatic invasion. https://doi.org/10.64898/2026.03.03.708913

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