Remi-Martin Laberge is a postdoc in Dr. Judy Campisi’s lab, and the first author of an exciting paper recently published in Nature Cell Biology titled “MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.” Remi and his coauthors showed that the MTOR inhibitor rapamycin blocks the senescence-associated secretory phenotype (SASP) by inhibiting translation of IL-1α, which prevents senescent fibroblasts from promoting cancer tumor growth.
SAGE sat down with Remi to discuss the main findings of this paper, and the implications that his research will have on the fields of aging and cancer.
1. How would you explain the main findings from this paper to the lay audience or say your grandmother?
What we found is that after chemotherapy or radiotherapy, cancer cells and the cells surrounding them become senescent. That means that the cells surrounding the cancer cells are no longer doing their normal function and they begin to secrete what we call cytokines and growth factors that stimulate cancer growth. We found that a small molecule called rapamycin can prevent this from happening. So if we extend the findings of that story, this drug may be useful following chemotherapy as an adjuvant. By giving the patient rapamycin after chemotherapy, we might slow down the relapse of the tumor. [Pause] I’m not sure if my grandmother would understand that, but I gave it a shot!
2. What’s the most significant finding from the paper?
Translational aspects are always exciting, so the potential application of rapamycin as an adjuvant in chemotherapy is a big one. But from a more mechanistic point of view, the most interesting finding was that rapamycin stopped the translation of IL1-α. This is a cytokine that is normally secreted as an immune response. In the case of senescent cells, IL-1α accumulates at the surface of the cell membrane, and this leads to a positive feedback loop of proinflammatory cytokine production. We can break that loop by stopping the translation of IL-1α with rapamycin. That also means that rapamycin will have a long lasting effect even after the drug is gone from the cells.
3. What were the technological or conceptual innovations from this study?
The techniques that we used were classic techniques of cellular biology and old school molecular and biochemistry. Polysome profiling* is a technique that was used in the 70s. And for a long period of time no one cared about translation and polysomes, but now in the past ten years there is a lot of excitement about this technique, so we’re using a combination of new and old technologies.
*mTOR is a master regulator of translation. mTOR will decide which transcript will have priority in terms of their translation. Rapamycin inhibits mTOR, so a subset of transcripts is less efficiently translated, and that includes IL-1α. Polysome profiling involves collecting RNA in a non-denaturing fashion such that the ribosome is still attached to the RNA. You then run the RNA on a sucrose gradient. The heaviest RNA (meaning it has the most ribosomes attached) will sink to the bottom and the lightest ones will stay at the top. Then you collect your fractions, you can separate them using qPCR to determine if a transcript is heavily translated (having lots of ribosomes attached), or only minimally translated (having few ribosomes attached).
4. How did you initiate the project?
I’ve been a postdoc here for almost 7 years, which is a long period of time. So when I arrived, it was not long after [Professor] Pankaj Kapahi arrived. Pankaj was a young investigator working on various translational projects. When he arrived, he started ‘’bugging’’ every postdoc in Judy Campisi’s lab saying, “You guys found the secretory phenotype of senescent cells: have you tried to put rapamycin on them? If you think senescent cells are implicated in aging, try rapamycin and see what it does to the SASP.”
Everyone said thanks for the idea but didn’t pursue it. At some point, I said. “OK I’ll give it a try. And I found that rapamycin was indeed reducing the secretory phenotype of senescent cells. So it all started with Pankaj! There was another postdoc Arturo Orjalo that tried rapamycin at the same time as me within a two week interval. We both did it without telling each other and presented our results at the same lab meeting; it was quite funny. After that lab meeting, we decided to collaborate on the project together.
5. What was the role of your collaborators in the project?
Pankaj was the inspiration of course, and within his lab, there were people who were tremendously helpful in developing some of the aspects. Su Liu was doing cancer growth stimulation in culture. Patrick Li was doing some of the polysome gradient experiments. When Patrick left, Kathy in Professor Chris Benz’s lab took over helping with the polysome profiling. In terms of collaborations outside of the Buck, there was Pete Nelson who is at the Fred Hutchinson Cancer Research Center. Pete was also working with rapamycin and is a long time collaborator with Judy.
Pete told Judy that he was working on rapamycin, and she said that we also had a similar project so we decided to work together. They the cancer experts that did all of the cancer and translational experiments. They work on a prostate cancer model, and they found that prostate cancer cells respond very strongly to SASP.
6. What’s next after this paper for this field?
The next step obvious step is to run a clinical trial with rapamycin or a rapalog. Rapamycin is already FDA approved, so this is exciting for clinical trials, but trials aren’t really something that basic scientists are equipped to do. Our paper is showing is that rapamycin would work well as an adjuvant therapy. So after you have received chemotherapy, senescent cells have been induced, and rapamycin can be used to block those otherwise harmful senescent cells. So rapamycin treatment should, in theory, delay relapse.
[We asked at this point if it was a concern that rapamycin is an immunosuppressant]
That’s always a good question to ask [laughs]! Rapamycin is labeled as an immunosuppressant. It is approved by the FDA for transplant rejection prevention. It prevents T-cell maturation. So when you receive a kidney transplant, you take rapamycin, and new T-cells do not mature, and therefore, nothing is there to attack the newly transplanted organ. So rapamycin is not an immunosuppressant in the classical sense of the term [it doesn’t kill existing T and B cells], but because it affects immune cells, it was labeled that way. In any case, no intervention is without risks. It is probably safe to say that in the case of cancer, the benefit of an intervention with rapamycin would largely outweigh the risk.
7. What were the major hurdles in completing this study?
The major hurdle was generating polysomes! Every time I needed a new round of polysomes, that postdoc that I was collaborating with had left. I should have learned the technique from the get go!
8. What’s next for you after this study?
I received positive comments after submitting this paper to Nature Cell Biology and these helped me to craft a strong application for a K99. I was successful in getting this grant, and one of the projects I proposed for it is a direct extension of this paper. The goal is to focus on one of the proteins downstream of mTOR: S6K2. This protein is not studied as much in the literature. S6K2 is important for blocking IL1-α translation, but we don’t know why.
9. How does the work relate to other findings from the lab or the Buck?
Half of the people at the Buck work in one way or another with mTOR. So everyone has some connection to translation or mTOR because of how important mTOR is in aging. We have various people working on different aspects of aging. Some are focusing on age-related pathologies, and others are working on aging in general using model organisms. I think that the Campisi lab fits somewhere in the middle because we work on cellular aspects of aging that can be applied to age-related pathologies but also to general aging in a sense of healthspan. We are connected to everyone. As long as there are senescent cells, this model could apply to everyone here.
10. What is the “big picture” of your findings and how will they impact the field of aging research?
We know that senescent cells accumulate at sites of age-related pathologies and in some pathologies that aren’t age related. We are still finding these things out. What is being taught currently is that the deleterious effect that senescent cells have is due to a proinflammatory profile. It is possible that rapamycin extends lifespan because it reduces the low level of chronic inflammation. So if you can think that this is true for aging in general, this could also be true for various age-related pathologies. It will be interesting to see the follow up on rapamycin and modulation of the proinflammatory profile of senescent cells.
I grew up in a small town called Chicoutimi in the northeastern part of Canada. It’s a French speaking region about 5 hours northeast of Montreal. I went to Sherbrooke to do my undergraduate and master’s in Biochemistry. After that, I went to McGill University in Montreal to do my PhD in cancer drug resistance. I joined Judy’s lab in 2008.
For more information on Remi’s publication check out the Buck Institute news release: