Aiden Deacon from the University of Minnesota-Twin Cities, Minneapolis, discusses a research paper he co-authored that was published in Volume 16 of Oncotarget, titled “Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.”
Behind the Study is a series of transcribed videos of researchers elaborating on their oncology-focused research published by Oncotarget. Visit the Oncotarget YouTube channel for more insights from outstanding authors.
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Hi, my name is Aiden Deacon. I’m a first year cancer biology PhD student who’s just starting this week actually at the University of Colorado Anschutz. I would like to thank the team at Oncotarget for giving me the opportunity to talk about our recent publication with them.
Over the past two and a half years, I’ve been fortunate enough to have worked in the lab of Dr. Justin Hwang at the University of Minnesota. Dr. Hwang’s lab takes a multiomic approach in order to interrogate novel regulatory genes driving various cancers whilst keeping clinical relevance at the forefront of the lab’s work.
In this recent publication, we looked into the functional differences and the clinical relevance of members of the R-spondin family in prostate cancers with taking specific regard to R-spondin 2. There are four R-spondins. They’re aptly named 1, 2, 3, and 4. To understand why we began this project, why is in the lack of viable therapeutic options for post-treatment resistance, prostate cancer patients?
Oftentimes patients will undergo surgery initially to try and resect the tumor. This will be followed by Androgen Deprivation Therapy, ADT, as we’ll call it. ADT is a great and viable option for patients. However, patients will eventually grow to resist this option. So at this stage, doctors aren’t really left with a lot of truly viable options. So that’s where Dr. Hwang and his team and myself come in to try and bridge that gap and provide some base level research in order to build and find novel therapeutic targets. So R-spondin 2 became a target of interest of ours for a few reasons, actually. One of those being a high rate of alterations, and then also its presence in the oncogenic Wnt pathway. And then due to the secreted nature of it that would allow if it was proved to be a viable target for easier antibody targeting because it exists outside of the cell.
So in the paper we see that RSPO2 is not just altered more frequently than the other R-spondins, but it is almost always overexpressed when it is altered. Even more interesting is that these alterations aren’t just abundant, but rather we see them actually leading to worse survival outcomes. So it’s not just a case of it’s altered, but it’s not really doing anything. These over expressions are leading to worse survival outcomes. This led to a suite of genomic interrogations as well as some assays to try and uncover the implications of this RSPO2 overexpression in various cell lines. One AR negative and one AR positive cell line. In these studies, we came across some really, really interesting and fascinating results, many of which come from RNA sequencing, which we were analyzing the transcriptome. Based on our transcriptional profiling performed on the cells with RSPO2 overexpression, R-Spondin 2 seemingly has some form of role to play in both epithelial mesenchymal transition, which we’ll call EMT for short and double negative prostate cancer subtypes, which we’ll call DMPC for short.
RSPO2 has been implicated before in EMT, but our connection to ZEB-I and TWIST-I, which are known EMT drivers appears to be a novel discovery. This is actually further corroborated when we see similar gene behavior profiles in patient samples of metastatic castration-resistant prostate cancer patients or MCRPC. Even more surprising, and frankly, maybe my favorite result that kind came out of this paper is that in these results and the overall transcriptional profiles, we found that the RSPO2 overexpressed cell lines were robustly different than the makeup of the CTNNB1 overexpressed cell lines. CTNNB1 is a key regulator in the Wnt pathway entering the nucleus and altering transcription. And so given RSPO2s believed role in the Wnt pathway, we hypothesized that these profiles would be decently similar. However, the robust difference between the two could be indicative of a potential role for RSPO2 and prostate cancers that exists outside of canonical Wnt signaling.
There’s actually a study from the Institute of Molecular Biology in Mainz, Germany from I think 2021, that indicates that an RSPO2 blockade mainly attenuated Autocrine BMP signaling, which furthers that idea that the function of RSPO2 may extend beyond just regulation of Wnt. So the next steps of this project have a near endless array of possibilities. I think that continuing to probe that potential RSPO2 outside of Wnt existence is a really fascinating avenue to kind of continue down. However, I think that what we’re going to be working on in the immediate is the potential relationship with EMT and specifically with DMPCs. We’ve actually begun to look into DMPC samples with regards to RSPO2 activity and trying to establish a baseline for what DMPCs look like in clinical samples.
As for me, I’ll be continuing my training here at Colorado and continuing to collaborate and work with Justin and his team at Minnesota so that the aforementioned project that’s a subsidiary of this can continue to exist and grow into another great paper that hopefully we can submit to Oncotarget as well.
With that, I want to thank the entire team at Minnesota who have allowed me to grow and learn so, so much, with special regards to Doctors Emmanuel Antonarakis and Justin Drake for providing crucial feedback throughout the entirety of this R-spondin project, as well as Alison Makovic for incredible contributions to the writing on this project. And finally, Justin Hwang, whose mentorship and guidance continues to allow me and those around him to do great impactful science like this aforementioned project.
Click here to read the full review published by Oncotarget.
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