Mouse Genetic Models of Sarcomagenesis
The Jones lab investigates the genetic and epigenetic underpinnings of cancer initiation—sometimes called transformation or oncogenesis—using sarcomas as model diseases and the mouse as host. The two principle contributions to the character of a cancer cell are the character of the normal cell from which it began (often called the cell of origin) and the genetic or epigenetic changes that changed it from a normal cell to a cancer cell (often termed the transforming events or just transformation.)
The tumor above, a peripheral chondrosarcoma just below the knee, devloped in a man who carries a mutated version of the EXT1 gene.
The peripheral chondrosarcoma seen just above the knee to the right was genetically induced by silencing the Ext1 gene in chondrocytes in the mouse.
The study of sarcomagenesis in genetic mouse models strives to understand these two inputs into the final character of the sarcomas that develop, hoping to identify unique cancer cell vulnerabilities that treatments may exploit.
At the heart of the study of both the cell of origin and the transforming events that drive it to become a sarcoma we find developmental biology. Often with only minor twists, the same molecular pathways that govern the process of a cell dividing and growing into a muscle or a bone or a limb also guide a cell's potential to be the origin of a tumor and the events to bring this change about. We therefore use the genetic tools of developmental biology to study sarcomagenesis.
Sarcomas Driven by Chromosomal Translocations
Chromosomes are the large conglomerations of DNA in which cells store their genetic code. A normal human cell has 46 chromosomes, existing in pairs. A translocation happens when an arm of one of these chromosomes breaks off and swaps positions with an arm of another. Each new translocated chromosome will have a new gene formed at the junction site. That new gene contains the beginning of one gene and the end of another. This fusion gene may display properties or function that neither parent gene had prior to the translocation.
About a third of sarcomas were found in the 1990s to associate consistently with specific balanced chromosomal translocations. These specific translocations were then noted to create unique fusion genes. Some of these fusion genes from human sarcomas have been expressed in mice and found to be capable of driving the formation of cancers that mimic their human counterparts. Such capacities render these fusion genes to function as oncogenes. Mice provide a powerful system to study how these translocation-created fusion oncogenes drive sarcomagenesis because other genes can be readily manipulated to test the importance of other pathways. Drugs can also readily be tested in these mice that develop bona fide tumors, rather than simply cell lines cultured in an immunocompromised mouse host.
The tumor above arose in the thigh of a young woman. It was found to express an SS18-SSX fusion oncogene, characteristic of the diagnosis of synovial sarcoma.
The tumor to the right arose in the forearm of a mouse that was induced to express an SS18-SSX fusion oncogene in mesenchymal progentior cells.
The Jones lab uses mouse models that can activate the expression of the SS18-SSX fusion oncogenes at specific times in specific tissues to model the development of synovial sarcoma, a deadly soft-tissue cancer with predilection for young adults. This model recently revealed a unique Achilles heel of this tumor in the mitochondrial apoptosis pathway, or the means by which cancer cells fight off death signals. Work is ongoing to prepare for translation of this knowledge into a clinical trial for patients.
The lab also works with models of other translocation associated sarcomas, such as Clear Cell Sarcoma and Alveolar Soft Part Sarcoma.
Sarcomas Driven by Loss of Tumor Suppressors
The majority of sarcomas (and most other cancers) are initiated when tumor suppressor genes are turned off by mutation or loss. These cancers have accrued rampant complexities by the time they are diagnosed; whatever are the initial mutations end up being masked by the subsequent development of many additional mutations and gene losses and gains.
Mouse genetics research permits two avenues of study for these complex genetic sarcomas. First, we can test whether or not the loss of a certain gene (or a certain combination of genes) in a certain cell type will lead to the development of a sarcoma or to the progression of a sarcoma initiated by simpler means. We call this the candidate gene approach. Second, we can activate disrupting tools that will randomly turn genes off, but in a traceable way. We call this a forward genetic screen. When tumors form in these mice, we find the traceable gene disruptions amidst the noise of the many other mutations, losses, and gains, judging the traceable disruptions to be "drivers" and the other derangements to be passengers.
The Jones lab uses both Sleeping Beauty and piggyBac transposon systems for these forward genetic screens to identify driver genes in osteosarcoma, the most common bone sarcoma and a major cause of adolescent and young adult cancer deaths. The lab also uses forward genetic screens to identify genes of interest for progression or metastasis in chromosomal translocation-driven sarcomas.
The tumor destroying the tibia above was induced in a mouse by silencing the Trp53 and Rb1 genes in pre-osteoblast.
The tumor consuming the distal femur above is an osteosarcoma that arose in a 13y.o. boy. These tumors typically demonstrate the loss of the TP53 and RB1 genes.
The Epigenetics of Sarcomagenesis
Especially in the case of translocation-driven sarcomas, massive shifts in the cell’s transcriptional landscape are achieved by singular genetic alterations. This conceptually hearkens to the capacity for the expression of four Yamanaka factors to reprogram somatic cells into a state similar to embryonic stem cells. A major focus of the Jones lab is on the mechanisms of epigenetic reprogramming, by which the expression of a single fusion oncogene drives an entire program of sarcomagenic transcriptional dysregulation. With what transcriptional machinery does each fusion oncoprotein partner to achieve its effects? How does it target specific genetic loci for upregulated or downregulated transcription? Are members of these complexes targetable by small molecules?