Abstract C067: Correlation of keratin17 expression with tumor cell proliferation and invasion in PDAC

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) shows variable degrees of differentiation, with both intratumoral, regional, and case to case heterogeneity, including glandular elements, sheet-like aggregates, cell clusters, and single diffusely infiltrative tumor cells. Prior research from our lab and others have established keratin 17 (K17) to be a defining hallmark of the basal molecular subtype of PDAC. In addition to its role as a component of the cytoskeleton, soluble forms of K17 undergo nuclear translocation to drive cell cycle progression and chemoresistance to first line chemotherapy. While K17 is heterogeneously expressed in the gland-forming elements of PDACs, it is most consistently expressed in tumor cells which are either in small groups or are single diffusely infiltrative. The aims of the current study are to define the correlation between K17 expression and tumor cell differentiation, with the focus on glandular versus single diffusely infiltrative components of PDAC, and to relate these findings to established biomarkers of cell proliferation and invasion. Methods: Archival human PDACs were provided by the Stony Brook Cancer Center Biobank and K17 immunohistochemistry was performed by indirect immunoperoxidase method, as previously described, to select cases with both glandular and diffusely infiltrative cell components and heterogeneous K17 expression. Multiplex immunofluorescence with a panel of antibodies to K17 (Cell Signaling Technology), pan-cytokeratin, Ki-67 and vimentin [KS1] (Miltenyi Biotec) was performed on 5-micron FFPE sections using the MACSima system (Miltenyi Biotec). Distribution patterns of K17 were evaluated in glandular and diffusely invasive components and were related to the Ki-67 status. Results: Cytoplasmic staining for K17 was found in the minority of tumor cells in glands and displayed intraglandular heterogeneity but was found in most diffusely infiltrative tumor cells. Also, nuclear K17 was rarely detected in the glandular components but was found in a high proportion of the diffusely infiltrative cells. Ki-67 was detected mainly in glandular cells, unrelated to K17 status, and rarely in single diffusely infiltrative cells, never co-localizing with nuclear K17. Of note, only a small fraction of tumor cells co-expressed K17 and vimentin, suggesting that majority of diffusely infiltrative tumor cells were not engaged in epithelial to mesenchymal transition. Conclusion: While cytoplasmic K17 is heterogeneously expressed in the glandular components of PDAC, strong staining for K17 in both the cytoplasm and the nucleus is a hallmark of diffusely infiltrative, Ki-67-negative tumor cells. These observations support the paradigm that tumor cells are committed to either cell division in the glandular components, or to diffuse single cell invasion, highlighted by increased cytoplasmic and nuclear K17 expression. Therefore, the results emphasize the importance of understanding the expression of PDAC biomarkers in both gland-forming elements and diffusely infiltrative tumor cells. Citation Format: Shayan Sarkar, Lyanne Oblein, Michael Horowitz, Luisa Escobar-Hoyos, Natalia Marchenko, Kenneth Shroyer. Correlation of keratin17 expression with tumor cell proliferation and invasion in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C067.