Michigan Cancer Research Fund                                                                                            American Cancer Society
   
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Research Project Description and Objectives from Ethan Abel, PhD, MCRF 2015 Fellow

Project Name:  The Role of HNF1A in Pancreatic Cancer Cell Biology

Pancreatic adenocarcinoma (PDA) has the lowest 5-year survival rate of any cancer (below 25% for patients with stage I disease and 1% for patients with stage IV disease). 46,420 new cases of PDA will be diagnosed in the U.S.A. this year, and will be the second leading cause of cancer deaths by 2020. The lethality of PDA is due to a number of factors, including a lack of early detection, aggressive metastasis to other organs, and a general lack of responsiveness to treatments such as surgery, chemotherapy, and radiation.

Our lab is focused on a subset of PDA tumor cells called pancreatic cancer stem cells (PCSCs). The first lab to identify these cells in PDA, we have found that PCSCs are responsible for tumor growth, metastasis, and resistance to chemotherapy, putting them at the heart of the malignancy of PDA. Similar to normal stem cells, PCSCs have the ability to undergo differentiation to various cells of the tumor, but unlike most differentiated tumor cells, PCSCs can also self- renew, maintaining their numbers while proliferating the tumor at the same time. PCSCs are also highly resistant to conventional treatment options, and are a source of recurrent disease after treatment.

Our initial observation regarding PCSCs is that they have an appearance and biological properties intermediate between the tumor cell types they differentiate into. To better understand what distinguishes these different cell subtypes, we performed gene-expression analyses and identified HNF1A as a gene highly expressed in PCSCs compared to their differentiated progeny. Additionally, manipulation of HNF1A in PDA cells altered a number of PCSC properties, including cell growth. We therefore predict that HNF1A is key to coordinating PCSC self-renewal and differentiation into other tumor cell types.

In our first aim, we plan to target HNF1A in PDA cells to determine if it is crucial for PCSCs to control differentiation as well as tumorigenesis. In our second aim, we look at how HNF1A regulates the response of PDA cells to suppression of KRAS, a gene mutated and hyperactivated in nearly all PDA. Resistance to KRAS suppression has been attributed to cells with PCSC-like properties, and we have found that HNF1A levels increase in response to targeting KRAS and may protect the cells as a result. We will alter the levels of HNF1A in a panel of PDA cells and test for changes in sensitivity to KRAS suppression using cell proliferation and death as readouts. Additionally, we will utilize a novel form of gene expression analysis to identify how HNF1A conveys resistance to KRAS suppression. We believe that the completion of these studies will improve our understanding of PDA biology and uncover novel therapeutic targets that will improve treatment of the disease.

Summer 2016 Update

The focus of my research is understanding the role(s) of the transcription factor HNF1A in pancreatic adenocarcinoma, the most common and deadliest form of pancreatic cancer. I have previously shown that HNF1A levels are elevated in a subset of pancreatic cancer cells called pancreatic cancer stem cells (PCSCs), which are important for tumor growth, drug resistance and metastasis. I have also shown that HNF1A levels are further elevated in pancreatic cancer cells by targeting the main oncogene KRAS (mutated in >90% of cases) and its downstream effector MEK1/2. Additionally, increasing levels of HNF1A in pancreatic cancer cells protects the cells from ablating KRAS signaling.

In the last year I have furthered these studies by demonstrating that ablation of HNF1A reduces pancreatic cancer cell growth in vitro, tumor growth in vivo, and PCSC numbers in both in vitro and in vivo. I have begun performing next-generation genomic and transcriptomic analysis of pancreatic cancer and normal pancreas cells to more globally examine HNF1A’s role(s) in both states of the pancreas, and have identified a number of direct target genes for HNF1A that may fuel future studies. Additionally, I am performing transcriptomic analysis of patient-derived pancreatic cancer cells treated with the MEK1/2-inhibitor Trametinib, which inhibits mutant KRAS signaling, with the hopes of understanding what HNF1A-regulated genes respond to KRAS-ablation and whether these genes are important in resistance to KRAS-ablation. I am also currently examining the expression of HNF1A across a large panel of patient samples to determine whether levels of HNF1A are predictive for patient outcomes. In the past year I have contributed to two accepted publications, with at least four more publications in progress including the above studies.