Fibrolamellar carcinoma (FLC) is a rare and often lethal form of liver cancer that usually affects adolescents and young adults without underlying cirrhosis. Currently, the only form of highly effective treatment is surgical resection, and there is no standard chemotherapeutic treatment for this cancer. Thus there is an urgent need for effective therapeutic strategies. The hallmark genetic mutation in this cancer is a fusion of two different genes, DNAJB1 and PRKACA, which encodes a protein chimera (DNAJ-PKAc) that is sufficient for tumor development in mice. While directly targeting and suppressing this fusion gene remains an important and active area of research, it has proven to be challenging to accomplish without highly undesirable off-target effects; therefore, it is critical to identify other new targets for therapeutic
intervention.

Like tumors of other cancer types, the microenvironment of FLC tumors is highly complex, comprising many different cell types. It is now well-established from investigation of other cancer types (such as lung, breast, and pancreatic cancer) that cross-talk among these different cell types can promote tumor development, growth, and spread. A recent study in our lab (Sethupathy) identified critical regions of the genome that are uniquely activated in FLC. These regions offer clues about the genes that might be most critical for the development of FLC. However, an important limitation of this work is that it was performed on bulk FLC tissue, which does not resolve different cell types, and instead treats tumor tissue as one whole unit. This means that we do not yet know the specific cell types in which these FLC genes are active. This represents a major knowledge gap. If we could learn the specific cell types in which FLC genes are active, we could then study the functions of these genes in FLC with greater precision, and develop more effective targeted therapeutics.

To help bridge this knowledge gap, the Sethupathy (Cornell), Yarchoan (Johns Hopkins), and Thomas (St. Jude Children’s) labs will participate in a collaborative research consortium to develop an FLC tumor “atlas”. We will leverage state-of-the-art genome-scale technologies to provide unprecedented resolution of the cellular and molecular landscape of FLC. This consortium brings together three groups with longstanding interests and experience in FLC research, as well as specific expertise in genomics and gene regulation (Sethupathy), clinical oncology (Yarchoan), and immunology (Thomas and Yarchoan).