The PBL is the clinical and basic research subdivision of the Pancreatic Surgery Group at MGH. Since its founding by Dr Warshaw in 1972, the Lab has published 86 peer-reviewed original papers in such journals as Nature, PNAS, and Gastroenterology, 18 reviews, more than three hundred abstracts, and seven book chapters. The focus of the basic and translational laboratory efforts is the molecular mechanisms underlying the initiation, progression, and maintenance of pancreatic disease and cancer, specifically the contribution of developmental genes. The laboratory also runs a robust clinical research program designed to evaluate the management and care of patients with pancreatic cancer and premalignant cystic lesions.
Basic Science Research
One Thousand Pancreatic Cancer Genomes
The laboratory is engaged in a collaborative effort with the International Cancer Genome Consortium, a worldwide initiative to sequence the genomes of cancers. This exciting collaboration focuses principally on the pancreatic cancer genome, aiming to sequence in their entirety 500 pancreatic cancer genomes and their normal matched controls. We hope that this work will be transformative for our insights into pancreatic cancer and that it will change the landscape of research and treatment of this disease in the near future.
Genetic Determinants of Cancer Stem Cell Function in Pancreatic Ductal Adenocarcinoma (PDAC)
Recent evidence suggests that cancer stem cell populations in some cancers are chemoresistant, and likely account for disease recurrence. We are utilizing a functional genomic approach to identify molecular targets of the cancer stem cell population of PDAC that may be employed in the development of novel therapeutics. Using a xenograft model of PDAC, a genome-wide RNAi screen will be employed to identify those genes required for the survival and tumorigenic potential of cancer stem cells.
Inhibition of Hedgehog Signaling in Pancreatic Cancer Affects Both Adenomatous and Stromal Compartments and Inhibits Tumor Angiogenesis
We have been investigating the effect of Hedgehog (Hh) pathway inhibition by small molecule antagonists on the tumor, its stroma and tumor angiogenesis in a xenograft model of pancreatic cancer. Hh pathway inhibition profoundly affects the stromal and adenomatous components of the tumors and inhibits tumor angiogenesis. We are currently investigating how inhibition of Hh signaling affects the balance of pro- and antiangiogenic factors secreted by cancer and stromal cells.
Differences in Cancer Cell Migration Using a Series of Microfluidic Devices: a) Primary vs. Metastatic PDAC Cells; b) Cancer Stem Cells vs. Non-Cancer Stem Cells of PDAC The intrinsic ability of cancer cells to migrate is the key mechanism of metastasis. The role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well defined. Better understanding of different characteristics in migration of PDAC cells will be a fundamental component of the metastatic cascade, and will lead to novel therapeutic strategies against metastatic cancer.
Sonic Hedgehog (Shh) Links Altered Developmental Programs to Pancreatic Neoplasia
Our preliminary data reveals that Shh, an important developmental gene, plays a critical and early role in the development of human pancreatic ductal malignancy. Misexpression of Shh in the pancreas results in the formation of tubular complexes that histologically and genetically resemble precursor lesions to invasive cancer. Our future line of investigation is to determine if Shh is sufficient to cause pancreatic cancer.
Lineage Analysis of Pancreatic Cancer
Ductal adenocarcinoma is the most common type of primary malignancy of the pancreas. Despite the ductal phenotype of most human pancreatic carcinomas, there is still considerable debate regarding the cell of origin of pancreatic adenocarcinoma, and it remains a critical unanswered question. Recent advances in conditional transgenic technology have provided tools for conclusively determining cell lineage in mice using targeted gene recombination. Genomically tagged mice will be subjected to pancreatic cancer induction. Cell-type-specific tags will finally allow determination of initiator cell type.
Characterizing the Role of Chronic Pancreatitis in the Formation of Pancreatic Cancer
Chronic inflammatory stimuli have been causally linked to the formation of pancreatic cancer. The majority of pancreatic ductal adenocarcinomas occur in the head of the pancreas. Sonic hedgehog (Shh), an important developmental signaling molecule, has been reported to be misexpressed in pancreatic cancer and is believed to play an early and critical role in the formation of this malignancy. We have been investigating the role of the Shh pathway in linking inflammation to the formation of cancer in the pancreatic head.
Plectin-1 as a Novel Imaging Marker in Pancreatic Cancer
We are in great need of specific biomarkers to detect pancreatic ductal adenocarcinoma at an early stage, ideally before invasion. We have found that plectin-1 is specifically expressed in preinvasive, invasive and metastatic pancreatic cancer and that a plectin-1-targeting imaging agent specifically detects primary and metastatic tumors in an in vivo mouse model of pancreatic cancer. Strategies designed to image Plec1 may therefore substantially improve detection and staging, thus contributing to improved resectability, prognosis and survival in PDAC.
Preclinical Investigation into the Effects of Shh Pathway Agonist and Antagonists on the Biologic Behavior of Pancreatic Cancer
This study aims to determine whether inhibition of this pathway using small molecule antagonists will have any significant impact on the biologic behavior of pancreatic cancer.
Lymphotrophic Supraparamagnetic Nanoparticles (LN-MRI) to Improve Staging of Pancreatic Cancer Patients
Surgical resection of early-stage pancreatic cancer offers the only possibility of long-term survival. The care of patients with localized pancreatic cancers would be greatly aided by methods to accurately predict the clinical course of patients considered for surgery. We are involved in a project to improve the pre-operative staging of these patients using a novel imaging tool, magnetic resonance imaging with lymphotropic superparamagnetic nanoparticles. Our clinical protocol is designed to determine whether this method will accurately predict the presence of lymph node metastases in patients with pancreatic cancer. In each patient we will measure other tumor parameters as well, such as tumor volume, microvascularity, and glycolysis. Outcome data at 3 years post-surgery will be collected on all study participants. Tumor specimens obtained at surgery will be analyzed to identify candidate biomarkers for the development of novel imaging targets for PanIN and PDAC.
Detection of Circulating Tumor Cells (CTCs) in Pancreatic Ductal Adenocarcinoma (PDAC) Using a Microfluidic Platform (CTC) Chip: Portal vs. Peripheral Circulation
Little is known about the biology and genetics of CTCs in pancreatic cancer because they have been difficult to capture in the peripheral circulation. Our investigation into circulating tumor cells (CTCs) is designed to give us insights into the biology of tumor cell dissemination in cancer patients. Understanding the biology and genetics of cells “in transit” may give us unique insights into the mechanisms underlying metastasis.
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