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Sabrina Spencer Cancer Research Awards | CU Cancer Center | Aurora, Colorado

CU Cancer Researcher Wins Two Awards to Study Drug-Resistant Cancer Cells

A Q&A with Sabrina L. Spencer, PhD.

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Written by Valerie Gleaton on March 22, 2021

Sabrina L. Spencer, PhD, is a CU Boulder researcher and a CU Cancer Center member. Spencer recently won two awards: the Damon Runyon-Rachleff Innovation Award (from the Damon Runyon Cancer Research Foundation) and the Emerging Leader Award (from The Mark Foundation for Cancer Research). The preliminary research she used to apply for the grants, "Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling," was published in Nature Communications on March 19, 2021.

We spoke to Spencer about the awards and how she plans to use them to further her research.

What is the focus of your research?

The work is about understanding where drug resistance comes from in cancer. It's a well-known problem, and it's particularly prominent with targeted therapeutics. These drugs usually work great at first, but then, after some time, there's relapse.

A lot of people have focused on trying to understand what mutations in those relapsed tumors make the drugs stop working. But in a way, that's a little too late. Because the question is, how did those cells survive in the first place to be able to acquire the mutations to become drug resistant? We wanted to look at the first few days of drug treatment to understand whether you can already see cells adapting in a non-genetic way in order to evade the drugs.

You’re watching cells become drug resistant in real time? How does that work?

We use time-lapse microscopy to study this process. We're particularly adept at time-lapse imaging of single cells, where we film single cancer cells over several days and watch them proliferating. Then we hit them with the drugs and watch the drugs block the cells from proliferating. Then, after a couple of days, we can see a subset of cells start proliferating again.

What sparked your interest in this research?

I've always been interested in outliers. And I've always been interested in cancer cells, because they have such an interesting mixture of adaptive and maladaptive features — features that make them proliferate faster but are an Achilles heel as well. I like the philosophical juxtaposition of combining that with this idea of outliers and heterogeneity. Every cell is unique. Even genetically identical cells aren't truly identical, because they could have a little more of protein X and a little less of protein Y at any given moment. When it comes to drug resistance, these chance events can make a cell an outlier on one particular day, and that could be the day the drug comes along. Now that cell has a completely different fate.

You just won two awards to further this research. What was that like?

I submitted a very similar grant application to both, because each funding agency only gives out a handful of these awards. I didn’t think this would be a problem, because I wasn’t expecting to get either one! Then I found out that I had gotten both and thought I’d have to choose between them, but when I reported my situation to the two foundations, they said, “Don’t you worry about it. We’ll sort it out.” And they decided to co-fund the grant.

How will you use the grant?

One of the things we saw about the cells that escaped the drugs — cells we have dubbed escapees — is that they have DNA damage. That's curious, because these drugs are not supposed to be mutagenic. So the first aim of the grant is to understand how these drugs are causing DNA damage. The second finding is the activation of a stress response pathway called ATF4. That pathway is super high in the escapees, but not the non-escapees and not the untreated cells. We know that if you knock that pathway down, you get fewer escapees, but we don't really understand what that pathway is doing for the escapees. Is it helping them escape the drugs? Or is it just helping them survive the stress of cycling in the presence of the drugs? So that's the second aim of the grant, to understand how this ATF4 stress response pathway is enabling or promoting drug escape.

Topics: Research, Magazine