Intentions for Bardeesy Lab Donation

TargetCancer’s grant to the Bardeesy Laboratory will support a series of projects relating to the understanding and treatment of cholangiocarcinoma. This work will likely impact other cancers in the future as well.

1. Genetic models. Recent studies have shown that most cancers in adults have a very large number of genetic changes. In addition, it is now apparent that cancers affecting a given tissue can have a very different behavior (such as distinct drug sensitivities and propensity to metastasize) based on which set of genetic alterations is present. Therefore, identifying which genetic changes are critical for cancer growth and how sets of such alterations work together is important both to better understand the disease and to develop improved strategies for treatment. These issues are of paramount importance for cholangiocarcinoma, where there have been no significant improvements in cancer therapy over the past decade.

Given the large number of candidate cancer-related genes identified recently, a key bottleneck is the determination of which genes are important and how they function. Dr. Bardeesy’s laboratory has developed mouse model systems that enable the rapid testing of a series of genes implicated in cholangiocarcinoma. These studies are enhanced by collaboration with other investigators at the Massachusetts General Hospital (MGH) studying the genetics of human specimens.

2. Hippo signaling and liver stem cells. All organs need to have regulatory mechanisms so that they maintain a strictly controlled size within the body. The liver is remarkable compared to other organs in that it has the capacity to repair itself and precisely restore its original size after injury. Dr. Bardeesy, Dr. Joseph Avruch, and colleagues at MGH have identified a biochemical signaling pathway, known as Hippo, as being a critical ‘checkpoint’ that controls the size of the liver. Mutations in genes within this pathway remove a barrier to growth resulting in abnormal cell division and eventually cholangiocarcinoma, as well as another type of liver cancer, hepatocellular carcinoma. Prior to the formation of cancer, there is an expansion of primitive cells with the properties of liver stem cells. Current studies are aimed at understanding ways to block the growth of cholangiocarcinoma cells with Hippo pathway defects and to relate defective stem cell control to cancer formation.

3. Epigenetic Control. Normal cells in the liver divide rarely and carry out specialized functions, such as producing enzymes that affect the way the body digests food and stores nutrients. These specialized cells are referred to as being differentiated. Rapidly dividing cancer cells on the other hand, are undifferentiated, using all their nutrients to divide. It is thought that the process by which normal cells develop into cancers involves a biochemical program through which differentiation is disrupted. A major aspect of cellular differentiation is the control of which genes can be turned on and off in a given cell, a process known as epigenetic control. There is a great deal of interest in identifying which epigenetic regulatory proteins contribute to the abnormal growth of cancer cells. Efforts are underway in the Bardeesy laboratory to define the key epigenetic alteration in cholangiocarcinoma. Blocking the function of such proteins by drugs could be an effective therapeutic approach that either kills the cancer cells or that promotes their differentiation, rendering them unable to sustain growth.

The Bardeesy Lab at Massachusetts General Hospital Cancer Center