Keratin 17 Defines an Epithelial-Mesenchymal Transition-Associated Migratory Cell State in Pancreatic Ductal Adenocarcinoma

Authors

Sarkar, S., Ghosh, M., Delgado-Coka, L., Powers, S., Sathian, R., Davuluri, R. V., Gong, X., Mak, M. V., Villar, J., Qi, X., Babu, S., Marchenko, N., Shroyer, K.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early invasion, metastasis, and therapeutic resistance that contribute substantially to its poor clinical outcome. Keratin 17 (K17) is a recognized marker of the aggressive basal-like subtype of PDAC and an independent predictor of adverse prognosis; however, the biological basis for this association remains incompletely understood. To define K17-associated cellular programs, we integrated single-cell RNA sequencing (scRNA-seq) data from 42 patients, Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomic data from 140 tumors, MACSima multiplex spatial imaging of 63 patients, dual-plex immunohistochemistry of 60 cases, and three-dimensional spheroid migration assays. Single-cell transcriptomic analysis demonstrated significant enrichment of epithelial-mesenchymal transition (EMT)-associated gene programs among K17-positive malignant epithelial cells. Consistent with this finding, K17-positive tumors in the CPTAC cohort exhibited enrichment of the Hallmark EMT pathway at the protein level. Among six candidate markers identified through transcriptomic analyses, laminin subunit gamma-2 (LAMC2) was the only candidate associated with K17 at every validation step. Tumors positive for both K17 and LAMC2 had significantly worse overall survival than double-negative tumors (adjusted hazard ratio = 2.53). Multiplex spatial imaging localized K17-positive cells predominantly to poorly differentiated tumor regions and demonstrated frequent single-cell co-expression with LAMC2. Whole-slide dual-plex immunohistochemistry further confirmed the association between K17 and LAMC2 and showed progressive enrichment of K17/LAMC2-positive tumor cells with increasing intratumoral histologic grade. Functionally, gain- and loss-of-function studies in three-dimensional PDAC spheroids demonstrated that K17 promotes migratory outgrowth, and differences in proliferation did not account for this effect. Collectively, these findings identify K17 as a marker of a poorly differentiated, EMT-associated migratory cell state in PDAC and provide functional evidence that K17 contributes to tumor-cell migration.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Oct 2026.

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