Explore This Laboratory
Pancreatic cancer is a devastating disease—only 6% of patients survive beyond five years after diagnosis. One of the hallmarks of pancreatic tumors is an abundance of non-malignant (non-cancerous) cells and extensive fibrosis, collectively referred to as the stroma. These non-cancerous components of the tumor promote the aggressive growth of cancer cells and act as a physical barrier to traditional chemotherapeutics.
The Liss Laboratory’s research is focused on identifying epigenetic mechanisms that drive pancreatic cancer and understanding how the components of the tumor stroma contribute to these events.
The Liss Laboratory operates the Pancreatic Tumor Bank at Massachusetts General Hospital. This clinically annotated biobank contains both normal tissue and tumors from more than 2,600 patients.
The research in the Liss Laboratory focuses on characterizing epigenetic regulators contributing to the formation and progression of pancreatic cancer. While the epigenetic mechanisms that regulate gene expression are diverse, we are primarily interested in those epigenetic factors that exert their effects through histones (the proteins that structurally organize the DNA of cells).
Our group employs xenograft tumor models derived from surgically resected patient samples and genetically engineered mice to look at epigenetic pathways in cancer cells as well as their contribution to the tumor stroma.
Epigenetic programs in PDAC
One of the major areas of focus in our research is investigating the contribution of epigenetics to the most common pancreatic cancer: pancreatic ductal adenocarcinoma (PDAC).
To identify epigenetic regulators important for PDAC, we have performed functional screens of more than 100 unique epigenetic factors to determine their role in the growth of orthotopic xenograft tumors. These screens helped identify candidate genes based on their functional importance, independent of their altered genetics or expression in tumors.
The BET family of chromatin adaptors
Through this work, we identified bromodomain and extra-terminal (BET) proteins of BET family members (BRD2, BRD3 and BRD4) as playing a role in PDAC. These proteins bind to acetylated lysines on histones to regulate the expression of genes. Employing short hairpin RNAs (shRNAs) and small molecule inhibitors of BET proteins, we have recently demonstrated that the BET family plays a critical role in the growth of PDAC cells in vitro and in vivo. The diminished activity of BET proteins also reduces the fibroblast content of the tumor stroma from xenograft and genetically engineered mouse models of PDAC.
BET proteins contribute to both the cancer and stromal compartments of PDAC tumors by influencing multiple key nodal pathways, including the regulation of the signaling protein Sonic hedgehog (SHH) and its downstream effector, GLI. Within the cancer cells, BET proteins function as transcriptional co-activators of GLI, a family of transcription factors with important roles in the progression of PDAC tumorigenesis. Our identification of the physical interaction of BET with GLI proteins adds to a growing list of non-histone targets of the BET family.
In addition, BET proteins function as key mediators of the tumor microenvironment by regulating the expression and secretion of SHH. Pharmacologic or shRNA-mediated inhibition of BET proteins in cancer cells reduces the expression and secretion of SHH, which reduces GLI activity in the tumor stroma.
The Liss Laboratory is currently focused on defining additional mechanisms by which BET proteins exert their effects on the tumor and characterizing the contribution of additional epigenetic regulators identified in our shRNA screen to the biology of PDAC.
Pancreatic Tumor Bank
The Liss laboratory operates the Pancreatic Tumor Bank at Massachusetts General Hospital. This clinically annotated biobank facilitates the development of translational and basic research projects for the Liss lab and its collaborators at the Mass General and throughout the scientific community. The biobank contains both normal tissue and tumor tissue, as well as white blood cells, serum and plasma from more than 2,600 patients. These specimens are clinically annotated with data regarding:
• Tumor pathology
• Patient and family history
• Surgical data
• Radiotherapy and chemotherapy information
• Cancer surveillance results
• Disease-free status and overall survival
This clinical data allows for the discovery of disease-related biomarkers and the selection of biologically relevant samples for molecular analysis.
In addition to this repository of patient tissue and data, the Pancreatic Tumor Bank has built a “living tumor bank” consisting of xenograft tumors derived from more than 90 different patients that are available for study. Matching low passage cell lines have also been established from 34 of these xenograft tumors. These patient-derived xenograft tumors and cell lines provide biological models for the characterization of molecular pathways that may be unique to histologic and genetic subsets of pancreatic cancer.
Comparative histology of patient tumors (top row) and the corresponding xenograft tumors (bottom row). Well-differentiated (Grade 1), moderately differentiated (Grade 2), and poorly differentiated (Grade 3) tumors are all represented in the living tumor bank.
We invite motivated researchers to join our team. If you are interested in joining the lab, please email us your CV and a short description of your research interests.
The research in the Liss Laboratory focuses on characterizing epigenetic regulators contributing to the formation and progression of pancreatic cancer.
- Principal Investigator:
- Andrew S. Liss, PhD
- Senior Investigators:
- Carlos Fernandez-del Castillo, MD
- Andrew Warshaw, MD
Pergolini I, Morales-Oyarvide V, Mino-Kenudson M, Honselmann KC, Rosenbaum MW, Nahar S, Kem M, Ferrone CR, Lillemoe KD, Bardeesy N, Ryan DP, Thayer SP, Warshaw AL, Fernández-Del Castillo C, Liss AS. 2017.
Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. PLoS One. 12(8):e0182855.
Rosenbaum MW, Cauley CE, Kulemann B, Liss AS, Castillo CF, Warshaw AL, Lillemoe KD, Thayer SP, Pitman MB. 2017. Cytologic characteristics of circulating epithelioid cells in pancreatic disease. Cancer Cytopathol. 125(5):332-340.
Yamaguchi J, Mino-Kenudson M, Liss AS, Chowdhury S, Wang TC, Fernández-del Castillo C, Lillemoe KD, Warshaw AL, Thayer SP. 2016. Loss of Trefoil Factor 2 From Pancreatic Duct Glands Accelerates Formation of Intraductal Papillary Mucinous Neoplasms. Gastroenterology. 151:1232-44.e10.
Saung MT, Sharei A, Adalsteinsson VA, Cho N, Kamath T, Ruiz C, Kirkpatrick J, Petal N, Mino-Kenudson M, Thayer SP, Langer R, Jensen KF, Liss AS*, Love JC*. 2016. A Size-selective Intracellular Delivery Platform. Small. 12: 5873–81.
Saha SK, Gordan JD, Kleinstiver BP, Vu P, Najem MS, Yeo J-C, Shi L, Kato Y, Levin RS, Webber JT, Damon LJ, Egan RK, Greninger P, McDermott U, Garnett MJ, Jenkins RL, Rieger-Christ KM, Sullivan TB, Hezel AF, Liss AS, Mizukami Y, Goyal L, Ferrone CR, Zhu AX, Joung JK, Shokat KM, Benes CH, Bardeesy N. 2016. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. Cancer Discov. 6:727–39.
Kulemann B, Liss AS, Warshaw AL, Seifert S, Bronsert P, Glatz T, Pitman MB, Hoeppner J. 2016. KRAS mutations in pancreatic circulating tumor cells: a pilot study. Tumour Biol. 37:7547–54.
Huang Y, Nahar S, Nakagawa A, Fernandez-Barrena MG, Mertz JA, Bryant BM, Adams CE, Mino-Kenudson M, Von Alt KN, Chang K, Conery AR, Hatton C, Sims RJ, Fernandez-Zapico ME, Wang X, Lillemoe KD, Fernández-Del Castillo C, Warshaw AL, Thayer SP, Liss AS. 2016. Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment. Clin. Cancer Res. 22:4259-70.
Nakagawa A, Adams CE, Huang Y, Hamarneh SR, Liu W, Von Alt KN, Mino-Kenudson M, Hodin RA, Lillemoe KD, Fernández-Del Castillo C, Warshaw AL, Liss AS. 2016. Selective and reversible suppression of intestinal stem cell differentiation by pharmacological inhibition of BET bromodomains. Sci. Rep. 6:20390.
Nakagawa A, Von Alt K, Lillemoe KD, Fernández-Del Castillo C, Warshaw AL, Liss AS. 2015. A method for fixing and paraffin embedding tissue to retain the natural fluorescence of reporter proteins. Biotechniques 59:153–155.