We propose to build and utilize a unique repository of biospecimens that are focused on early pancreatic lesions by assembling a unique and robust collection of early lesions and blood samples from patients at risk and those with lesions representing early stages of pancreatic cancer, matched sets of tumors and metastasis and control tissues from the same patients, and in many cases longitudinally obtained blood samples from the same patients. We will include longitudinally obtained samples from patients at risk for developing pancreatic cancer that go on to develop pancreatic cancer, including patients with cystic lesions, chronic pancreatitis, and adult onset diabetes. This unique resource will be used to identify and characterize biomarkers that develop during the progression from premalignant lesions to primary tumors, and to evaluate blood samples from these patients for the presence of biomarkers at both early and late stages of disease progression. Both the biospecimens and candidate biomarkers will be available for collaborative studies within the Pancreatic Cancer Detection Consortium. Specific 1. We will establish a comprehensive collection of tissues (fixed, frozen and living as organoids) representing the spectrum of premalignant to malignant and metastatic lesions that occur within individual patients obtained at autopsy and at surgery, and develop a collection of longitudinally obtained blood and tissue specimens from patients at risk for pancreatic cancer and that develop pancreatic cancer.
Specific Aim 2. We will evaluate 15 novel glycoprotein biomarkers of pancreatic cancer progression in human tissue samples containing cell types that represent the progression of pancreatic cancer from early premalignant lesions to primary and metastatic cancer.
Specific Aim 3. We will evaluate the expression of 15 novel glycoprotein biomarkers of pancreatic cancer progression in longitudinal samples serum and plasma of patients that develop pancreatic cancer, and compare these to longitudinal samples of appropriate patients with benign diseases.
Specific Aim 4. Discover cell surface antigens specific to the malignant state by applying phage- display approaches to human pancreatic organoids.
Specific Aim 5. To evaluate and discover exosome-based biomarkers of pancreatic cancer by using an unbiased proteomic analysis of exosomal cargo derived from patients with early stage pancreatic lesions (PanIN3 eand early stage tumors) to develop a panel of markers that can accurately predict the progression of these lesions towards pancreatic cancer.
There are two overall goals of this project. The first is to assemble a unique and robust collection of early lesions and blood samples from patients at risk and those with lesions representing early stages of pancreatic cancer, matched sets of tumors and metastasis and control tissues from the same patients, a tissue resource for use in the discovery and validation of biomarkers for early disease. The second goal is to undertake a series of biomarker discovery and prevalidation projects, proposed within this application and by collaborative studies from other investigators that are part of the Pancreatic Cancer Detection Consortium.
|Qi, Bowen; Crawford, Ayrianne J; Wojtynek, Nicholas E et al. (2018) Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer. Nanomedicine 14:769-780|
|Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86|
|Nimmakayala, Rama Krishna; Batra, Surinder K; Ponnusamy, Moorthy P (2018) Unraveling the journey of cancer stem cells from origin to metastasis. Biochim Biophys Acta Rev Cancer 1871:50-63|
|Aithal, Abhijit; Rauth, Sanchita; Kshirsagar, Prakash et al. (2018) MUC16 as a novel target for cancer therapy. Expert Opin Ther Targets 22:675-686|
|Barkeer, Srikanth; Chugh, Seema; Batra, Surinder K et al. (2018) Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis. Neoplasia 20:813-825|
|Wang, Gang; Biswas, Anup K; Ma, Wanchao et al. (2018) Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat Med 24:770-781|
|Zhang, Haiying; Freitas, Daniela; Kim, Han Sang et al. (2018) Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol 20:332-343|
|Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana et al. (2018) Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 155:1608-1624|
|Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat et al. (2018) Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis 39:522-533|
|Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129|