Abstract 1754: A new glycan biomarker for pancreatic cancer complements CA19-9 and identifies a distinct subpopulation of cancer cells

Abstract

Abstract A major challenge in diagnosing and treating pancreatic cancer is the complex diversity between and within tumors in cellular morphologies and behaviors. Molecular markers to detect and classify specific variants of cancer cells could facilitate drug targeting of subtypes of cancer cells. We recently found that a glycan related to the CA19-9 antigen is a strong serological biomarker and is elevated in the plasma of about half of the patients with low CA19-9. We hypothesized that the cancer cells producing CA19-9 are a different subtype than those producing the new biomarker, referred to as sTRA. Using multimarker immunofluorescence on tissue microarrays, we found that sTRA was significantly elevated (p < 0.001) in tumor tissue relative to adjacent pancreatic tissue in 3 separate TMAs covering 38 patients. The sTRA and CA19-9 markers were present in 31/38 (82%) and 20/38 (53%) of the tumors, respectively, with 17/38 (45%) displaying both and 3/38 (8%) displaying neither. The morphologies of the cancer cells fell into distinct categories based on glycan expression. Cells with dual staining of both markers tended to be in well-to-moderately differentiated ducts with good nuclear polarization and foamy cytoplasm, or with flat and thin epithelium. Cells with predominant or exclusive CA19-9 staining tended to be part of well-differentiated ducts with mucinous cytoplasm or moderately-differentiated ducts with poor membrane integrity. In contrast, strong sTRA staining was present in small clusters of cells or single cells with poor differentiation and large vacuoles, or in small and invasive ducts. The phenotypes were consistent in xenograft models made with either cells lines or patient-derived material, as well as in 2D culture. Costaining with protein markers of differentiation showed that the CA19-9-positive/sTRA-negative regions colocalized more with MUC5AC, CK19, and E-cadherin relative to the sTRA-positive cells, indicating ductal differentiation, and the sTRA-positive/CA19-9-negative regions were more likely to colocalize with beta-catenin than any other marker, indicating potential for anchorage-independent growth or altered cellular cohesion. The time-to-progression after surgery was associated with the relative levels of the two markers, based on staining of tumors from 48 patients in an independent TMA. Patients with higher dual-staining of CA19-9 and sTRA had statistically longer (p = 0.01 by log-rank test) time-to-progression, and patients with higher exclusive staining of either marker relative to the dual staining had shorter time-to-progression. Thus the sTRA marker used in conjunction with CA19-9 could provide a basis for classifying and targeting subtypes of cancer cells. Citation Format: Daniel Barnett, Ying Liu, Katie Partyka, Galen Hostetter, Herbert Zeh, Aatur D. Singhi, Ying Huang, Richard R. Drake, Randall E. Brand, Brian B. Haab. A new glycan biomarker for pancreatic cancer complements CA19-9 and identifies a distinct subpopulation of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1754. doi:10.1158/1538-7445.AM2017-1754