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  • Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Nature communications (2021-05-26)
S Dhara, S Chhangawala, H Chintalapudi, G Askan, V Aveson, A L Massa, L Zhang, D Torres, A P Makohon-Moore, N Lecomte, J P Melchor, J Bermeo, A Cardenas, S Sinha, D Glassman, R Nicolle, R Moffitt, K H Yu, S Leppanen, S Laderman, B Curry, J Gui, V P Balachandran, C Iacobuzio-Donahue, R Chandwani, C S Leslie, S D Leach
ABSTRACT

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ZKSCAN1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Kolliphor® P 188, solid