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About the Authors:
Surabhi Dangi-Garimella
Contributed equally to this work with: Surabhi Dangi-Garimella, Vaibhav Sahai
* E-mail: [email protected] (SD); [email protected] (HGM)
Affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
Vaibhav Sahai
Contributed equally to this work with: Surabhi Dangi-Garimella, Vaibhav Sahai
Affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
Kazumi Ebine
Affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
Krishan Kumar
Affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
Hidayatullah G. Munshi
* E-mail: [email protected] (SD); [email protected] (HGM)
Affiliations Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America, Jesse Brown VA Medical Center, Northwestern University, Chicago, Illinois, United States of America, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, Illinois, United States of America
Introduction
Despite tremendous efforts, the progress made in the treatment of pancreatic ductal adenocarcinoma (PDAC) has been frustratingly scant [1], [2]. PDAC continues to remain the fourth leading cause of cancer-related deaths in the US, with an ∼80% one-year mortality for most patients [3]. This lack of progress is in part due to the pronounced collagen-rich fibrotic reaction associated with PDAC tumors [4], [5], which subsequently limits the delivery and efficacy of chemotherapy [6], [7], [8], [9]. Recently, we published that PDAC cells in the three-dimensional collagen microenvironment induce high mobility group A2 (HMGA2), an architectural protein that regulates chromatin structure and also mediates chemo-resistance in the collagen-rich microenvironment [6], [10], [11]. Significantly, HMGA2 is upregulated in human PDAC tumors, particularly in high-grade tumors with lymph node metastases [12], [13].
PDAC is also associated with epigenetic changes, which have been linked to patient prognosis [14], [15]. Post-translational histone modification patterns detected by immunohistochemistry were shown to be predictive of prognosis in two large cohorts of PDAC patients treated with chemotherapy [14], [15]. PDAC patients whose tumors demonstrated a low expression of histone H3 lysine 27 tri-methylation (H3K27Me3) or histone H3 lysine 9 di-methylation (H3K9Me2), which are marks of closed chromatin (‘heterochromatin’) and gene...