3D Multiscale Analysis of Malignant Progression in Human Pancreatic Cancer
Abstract
Pancreatic cancer, a highly lethal disease, arises from precancers that are in fact curable if detected and treated early enough. We directly address the FY21 PCARP Focus Area understanding precursors, origins, and early progression of pancreatic cancer by proposing an innovative approach toward understanding the key transition point in pancreatic tumorigenesis: The progression from a curable precancerous neoplasm to an incurable invasive cancer. Although this malignant progression is a critical step leading to poor outcomes in pancreatic cancer, little is known about the molecular and cellular alterations that underlie the transition from precancer to invasive cancer. Addressing this gap in knowledge has been particularly challenging due to the limitations in the assay precision and the inherent two-dimensional nature of histology specimens. Herein we now propose to (i) integrate cutting-edge, high-parameter analysis methods to interrogate precancers and (ii) undertake three-dimensional reconstructions of well-characterized human pancreatic tissue samples to more precisely determine the drivers of malignant progression in pancreatic cancer. By integrating tumor genetics and tumor microenvironment features in patient-matched precancer lesions and invasive cancers, we propose to determine the molecular and cellular processes underlying the transition. Specifically, we will test the hypothesis that pro-invasion processes mediated by TGFbeta and IL6 will be enriching the presence of immunosuppressive myeloid cells in progressive precancers and at points of invasion. Moreover, in overcoming the limitations of two-dimensional evaluation of cancer invasion, our studies will be uniquely enhanced by our recently developed method of fully reconstructing human pancreatic tissue in three dimensions. Based on three-dimensional guidance, we will identify the precise point at which a precancer invades the surrounding stroma and assess the tumor microenvironment at that point. This project will establish an important proof-of-concept in the utility of integrating alterations in both the tumor cells and the microenvironment and employing three-dimensional analysis to understand mechanisms of pancreatic cancer invasion. Since we will be determining molecular and cellular processes based on three-dimensional morphological guidance in real human pancreatic tissue samples, discovery of biomarkers that signify precancers at high risk of invasion, and thus in need of surgical resection, will be robust. In addition, our proposed analysis of genetic and cellular alterations together has the potential to yield novel strategies in an unbiased manner for the prevention of malignant progression in precancers. Successful completion of the proposed studies will lead to deeper mechanistic understanding of early pancreatic cancer progression, promise toward preventing pancreatic cancer in at-risk patients, and also invaluable methodological advances that has the potential to empower cancer research at large.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210771
Entities
People
- Laura Wood
Organizations
- Johns Hopkins University
- United States Army