Cairns Lab - Chromatin Cancer Connections

Our scientific program connects to cancer in many ways.

First, mutations in SWI/SNF-family complexes (also called BAF complexes mammals) are found in ~20% of human tumors. This makes SWI/SNF complex the third or fourth most mutated entity in human cancer. These include recessive loss-of-function mutations that prevent SWI/SNF(BAF) targeting or activity. However, we recently found a set of dominant gain-of-function cancer-causing mutations that map to the regulatory ‘hub’ region of the ATPase motor. These mutations all cause the upregulation of DNA translocation and increased nucleosome sliding (Clapier et al., Molecular Cell 2020), suggesting that precocious nucleosome sliding—and linked transcriptional misregulation—likely underlies these cancers.

This work is in an exciting phase where we are learning much more each year about how the spectrum of cancer-linked mutations impacts SWI/SNF functions such as targeting or regulation, and leads to epigenetic variation. Here, we are adapting our mechanistic biochemistry on yeast SWI/SNF complexes in yeast to human SWI/SNF to better understand the regulation of human SWI/SNF. Thus, our mechanistic work has and will further inform the field about the normal modes of targeting and regulation of SWI/SNF—modes that might be misregulated in cancer.

Another way that SWI/SNF(BAF) complexes are mutated in cancer involves the creation of oncogenic fusion proteins which incorporate into the complex to provide dominant mis-targeting or dysregulation. A prominent example is the SS18-SSX fusion family, which is the cause of synovial sarcoma. The SS18 protein is a member of the BAF complex, but fusion to SSX dysregulates this complex. Recently, we collaborated with Kevin Jones’ lab at Utah to publish the mechanism of dysregulation, which involves the oncogenic fusion protein leading to the destruction of particular BAF complexes, while leaving others in greater proportion—changing the balance of chromatin remodeling in the cell, and impacting chromatin openness and transcription (Li & Mulvihill et al., Cancer Discovery, 2021). We are now reconstituting both normal and oncogenic versions of these complexes to learn more about their unique functions and mechanisms, and misregulation in cancer.

DNAme Reprogramming

We are also adapting our work on DNAme reprogramming to investigate tumors of particular relevance to the cancer center’s catchment area—paragangliomas—neuroendocrine tumors which occur at higher incidence at elevation.

These tumors often have mutations in succinate dehydrogenase and therefore accumulate succinate, which can inhibit key enzymes that utilize alpha-ketoglutarate, which in turn misregulates both histone and DNA demethylation systems.

We are collaborating with Dr. Josh Schiffman’s lab here at HCI to better understand the epigenetic and transcription status of these tumors.

Studying Germline Stem Cells to Understand Germ Cell Tumors

We are also adapting our work on germline stem cells to better understand germ cell tumors.

In the male, these tumors come in many types which are histologically distinct, and have different genetic and transcription profiles.

Germ cell tumors include teratomas, which form heterogeneous tissues from all three germ layers—which speaks to the embedded pluripotent developmental potential of germ cells.

What Do We Know About Germ Cell Pathways?

Remarkably little is known about the pathways that prevent germ cell tumor formation or the pathways—intrinsic or extrinsic/niche—that normally keep germline stem cells aligned to their normal identity and fate and prevent expression of their embedded pluripotency.

However, we know very little about the normal development and signaling pathways of germline stem cells—a prerequisite to understanding cancer development.

Therefore, we have made a major effort over that past several years to conduct a genomic analysis of normal germline stem cell development.

Our results, both in adult germline stem cells (Hammoud et al., Cell Stem Cell 2014) and in neonates and juveniles (Hammoud et al., in preparation) have provided considerable insight—and linked germline stem cell regulation to multiple signaling pathways important in cancer—which we are now beginning to adapt to understanding germline tumor formation.