Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and deadly cancer of young women and children. In order to bring hopes to defeat this disease, Dr. David Huntsman’s team have been working closely with Dr. Jeffrey Trent at the Translational Genomics Research Institute (TGen) and Dr. Bernard Weissman at the University of North Carolina through a joint research grant from the National Institutes of Health since 2014. They have discovered that the majority of SCCOHT is characterized by simultaneous inactivation of SMARCA4 and SMARCA2, two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex, through genetic and epigenetic mechanisms respectively, which have been adopted as definitive diagnostic markers for the diagnosis of SCCOHT. This work, published in the Journal of Pathology in 2016 (Karnezis, Wang and Ramos, et al), has been awarded the 2017 Jeremy Jass Prize for Research Excellence in Pathology by the Editorial Team of the Journal (see below).

On October 26 and 27, these three research groups held their bi-yearly team grant retreat in Vancouver to provide updates on the latest findings in their research. They have recently discovered that loss of SMARCA4/SMARCA2 caused an addiction of SCCOHT cells to the enzymatic activity of a protein called EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), a different chromatin remodeling complex. This work has been just published in the Journal of Pathology (Wang et al). Based on this discovery and a similar independent discovery by Epizyme Pharmaceutics (Chan-Penebre et al. 2017), clinical trials are now underway to evaluate the efficacy of EZH2 inhibitors in SCCOHT patients. In addition, our collaborative team has found that an FDA-approved multi-kinase inhibitor, called ponatinib, is effective in various pre-clinical models of SCCOHT (Lang and Hendricks et al, manuscript in revision), which could represent another potential treatment opportunity for patients.

In addition to the studies on SCCOHT, the three groups are also studying how mutations in other components of the SWI/SNF chromatin remodeling complex lead to the development of other malignancies, such as rhabdoid tumors, ovarian clear cell carcinoma, de-differentiated endometrial carcinoma and chordoma. These proposed activities will likely involve more scientists from our department, such as Drs. Cheng-Han Lee and Stephen Yip.

As a researcher, sometimes you just need to get out of Dodge. The daily grind of fighting the same old traffic to get to the office, time-pressured grant-writing, attending stultifying meeting after meeting, rushing to student committees, and answering endless “urgent” Emails from colleagues and administrators, can sap the creative spirit from most scientists. So, what can you do about it? Well, it’s obvious, go on sabbatical! That’s exactly what I did. UBC has a wonderful sabbatical system for Professors, 6 months for every 7 years of duty, but many of us don’t take advantage of this great opportunity to recharge, or even to change our focus a bit.

So, I packed up the family (wife, Carmen, youngest kid, 9 year old Anika, and even the dog, Chester, a 3 year old Golden Retriever), and went to Munich for 10 months from September, 2016 to June, 2017. Why Munich? First, Carmen is German-born and speaks the language. Second, Technical University Munich (TUM), the highest ranked research university in Germany, actually offered me a Professorship, called an August-Wilhelm Scheer Gastprofessorship from the Institute of Advanced Studies at TUM, for foreign Professors, and designed to forge collaborative links with TUM Professors. My host was Prof Stefan Burdach, Chair of Pediatrics and Pediatric Hematology/Oncology at TUM, one of the top pediatric oncology departments in all of Europe. Prof Burdach is a renowned expert in Ewing sarcoma, one of the tumour types that we are deeply interested in (more on that below). So, we found a house with a yard (not so difficult, as there are lots of websites), filled out endless bureaucratic forms (wow, in Germany even dogs are expected to read the rules; see Figure 1), bought a car (German, of course), sent Anika off to German-speaking Grundschule (she did great there), and Carmen got to reconnect with her German heritage for a while.

So, what did I do there? Well, they gave me an office and a computer. Having the time to actually think, I got the opportunity to focus on some questions in Ewing sarcoma research that I believe are really important. Ewing sarcoma is a highly aggressive bone and soft tissue sarcoma most commonly affecting children and young adults. The disease is driven by pathognomonic translocations fusing the EWS gene (chr22) to an ETS family transcription factor gene, most commonly FLI1 (chr11) in 85-90% of cases, or the chr21 gene, ERG, in 10-15% of cases. Even knowing this, outcomes for Ewing have been largely unchanged for the past two decades, partly because we do not understand the molecular basis of metastasis in this disease, which is the single most powerful predictor of poor outcome in Ewing sarcoma. This does not appear to be related to expression of EWS-ETS fusions, which are found in both localized and metastatic disease. So, working with Prof Burdach, we thought a lot about what might be driving Ewing sarcoma metastasis. Being relatively quiet at the genomic level, we reasoned that other mechanisms might be at play. My lab has a longstanding interest in how mRNA translational control is involved in adaptation to microenvironmental stress in tumours (e.g. doi: 10.1016/j.cell.2013.04.055 and doi: 10.1016/j.ccell.2015.04.003), and we have previously shown that formation of RNA aggregates in the cytoplasm called stress granules is important for tumour progression in sarcomas (doi: 10.1083/jcb.201411047). Under stress conditions such as oxidative stress or hypoxia, mRNAs are sequestered and silenced along with RNA binding proteins in cytoplasmic stress granules (stress granules, guardians of tumour cell fitness under harsh environments? Figure 2). This reduces overall mRNA translation and protein synthesis to save energy, but with selective translation of what we believe are largely stress adaptive mRNAs to synthesize proteins designed to protect cells from stress. This is a highly conserved process, and stress granules have even been observed in yeast. So, over countless excellent Munich coffees, and yes, many 1 litre beers in Munich biergartens (not hard to find), Prof Burdach and I came to realize that maybe one area we should be focusing on more in our research is the role of stress granules in Ewing sarcoma metastasis. It has long been postulated that metastasis is a highly inefficient process, with only a very small percentage of micrometastatic cells having the potential to survive the many stresses of the metastatic cascade to form distant metastases. Maybe stress granules provide tumour cell fitness for survival under metastatic stress. This has prompted me to embark, with renewed enthusiasm, on the role of stress granules in Ewing sarcoma progression, the goal being to better understand the process as a way forward to identify new targets to block or reverse the process. I think that, if successful, this could have profound implications for developing novel therapies to prevent or treat metastatic Ewing sarcoma. In fact, Prof Burdach and I have written some grants together and are working on several manuscripts focused on this concept.

The sabbatical wasn’t just about the science. We made great new friends, traveled around Europe (Munich is so central), skied many times in the Alps (Ah, St. Anton in the Austrian Alps; Figure 3), and I even learned a bit of German (Jawohl, mein Schatz). And yes, there was Oktoberfest (Carmen, Anika, and Poul, good Bavarians on the way to Oktoberfest; Figure 4). The punch line of this little narrative--we work hard in this business, and so take advantage of one of the real perks. Go and do a sabbatical, if you can, and rediscover your inner scientist, and come back with renewed vigor. Even your students will forgive you (eventually) when you bring back lots of new ideas for them to work on.