Transcription:
The Molecular Side of Esophageal Diseases

Dr Pam Peeke (Host): Hi, this is Better Edge, a Northwestern Medicine podcast for physicians. I am Dr. Pam Peeke. And today, we are discussing the molecular side of esophageal diseases. We are joined by Dr. Marie-Pier Tetreault. She is a PhD Assistant Professor of Medicine in the Department of Gastroenterology and Hepatology at Northwestern Medicine. Dr. Tetreault, can you please introduce yourself and tell us a little bit about your background? What are you doing in your lab?

Dr Marie-Pier Tetreault: My background is, by training, I'm a molecular biologist. My whole career I've been training and researching in gastroenterology. Most of my career, I've been focusing on the esophagus, which is very understudied in our field, especially at the molecular level where there's really a big need. So I have a unique background and expertise that allows us to push that. And being at Northwestern was a great opportunity for me, because as most of you probably know, we have some of the best clinicians that are investigating these diseases from the clinical side. Our lab is trying to complement what our great clinicians are doing, and really tried to push understanding what's happening with these diseases so that we can get better outcomes for the patients.

Dr Pam Peeke (Host): That's fantastic. And you know, you're absolutely correct, esophageal disease is somewhat understudied there. And this is so important for clinicians because we're talking about implications for esophageal cancer, eosinophilic esophogitis, scleroderma, esophageal disease and achalasia. So, kudos to you and your laboratory for really addressing these very tough issues.

Now, you just had a publication in cellular and molecular gastroenterology and hepatology. Tell us a little bit about this.

Dr Marie-Pier Tetreault: Yes. This study is a followup of an initial study that we had published in gastroenterology where really the interest in our lab is this connection of inflammation, which is very central to all esophageal diseases. And this main central mediator of inflammation, that is called IKK beta. What we found is that IKK beta is really on its own central to really initiate in the context of injury an inflammatory response. And in this study, what we've found is that actually there was a cross-talk with the other master regulation of inflammation called STAT3 and how this cross-talk really is important in regulating the recruitment of neutrophils.

As you know, neutrophils are important in the initial response when there's an injury to really try to help getting things under control and so this is what this study has been focusing about. And the interesting part of this study is that we found that really what's connecting these two pathways is the release of IL-23, which is really becoming a therapeutic targets, that is under a lot of scrutiny and studies, and its implication has been coming up in a lot of diseases.

Dr Pam Peeke (Host): Tell us more about that though, because I'm sure clinicians are thinking to themselves as a therapeutic target. Tell us more about where we might see an expansion of this.

Dr Marie-Pier Tetreault: Yes, that's a very good question and that was one of the challenge sometimes with this study, because it's extremely hard to capture the early stage of an injury. But what we found is that there are reports in the literature that high amount of neutrophils are seen in very chronic cases of gastroesophageal reflux disease. We also see them in the early stage, and that's what we looked into in our study in the early stages of an injury prior to getting esophageal cancer. And as we know, the outcomes for esophageal cancer patients is really poor. Survival rate over five years is less than 20%. And the problem is that then we're really limited in the extent of biopsies that we can get from these patients. So we were able to see these changes in both IKK beta and STAT3 and the neutrophils in samples from patients in adjacent areas where there was no cancer but high levels of inflammation.

Dr Pam Peeke (Host): What does that mean to a clinician then, if you can see this that early?

Dr Marie-Pier Tetreault: So we're hoping that this is going to allow to get things under control earlier. We still have yet to follow up with these studies to see in extreme cases of where do you see extreme infiltration of neutrophils, where things potentially could get under control. There's also candida esophagitis. This could mean once we investigate a little further, that we could potentially target IL-23 to try to get the number of neutrophils under control. And so therefore, we believe and that's why we need another study to be able to do this, but really looking more into IL-23 and considering it as a therapeutic in the future in cases where you see high amounts of neutrophils, where the injuries are not being resolved, so that over time we decrease the chance for patients to just progress in their diseases and, in the case that we looked into, potentially esophageal cancer.

Dr Pam Peeke (Host): I see. Okay. So this is really important, that we know that there's a high mortality rate with esophageal cancer, for instance. We also know that the epithelial barrier is host's first line of defense against damage to the underlying tissue. And that's why it's important to be able to see early on what's going on. And now, you've given us another method of being able to do that. That is excellent. That's fantastic. So, were there other discoveries that you noted in your study that you found to be compelling for clinicians?

Dr Marie-Pier Tetreault: You just brought up this whole concept of the epithelium and the barrier. This is also the angle that's different that's taken by our lab. When you think about inflammation, everybody focuses on immune cells, which makes absolute sense, but the point that we're making here and how we're trying to change things, it's really because the epithelium is the first layer of cells that's exposed to any changes, infections, reflux, we really want to make the statement that early on, this is where everything starts and they are playing a central role in orchestrating all this inflammatory response.

So this is the other major highlight of our studies, especially in the case of IKK beta, NF-kappa B signaling. Most of the studies for years were solely focusing on immune cells and not really looking at cell's specific effects. It's not from this study, but this leads us also to really look at these inflammatory mediators because now we have models in the lab where we can induce specific esophageal diseases and take the same approach to really look in each context what's happening with the signaling so that we can come up with better therapeutics, again focusing on manipulating only in the epithelium.

Dr Pam Peeke (Host): That is so fabulous. Again, it's another really novel tool to be able to pivot and look at epithelium instead of just immune cells, as you've said, and to really keep in mind, let's look at the context here, I think it's really important to remember that esophageal squamous cell cancer accounts for more than 90% of esophageal cancer. And, as you said, it develops progressively from inflammation, hyperplasia, dysplasia, carcinoma in situ and then to invasive carcinoma. I think that your concentration on epithelial cells as the first line of defense for the esophagus is incredibly important, because we all know in clinical medicine that it's the epithelial cells themselves that are constantly challenged by exposure to irritants like alcohol, tobacco, food antigens, gastric acid reflux, and more. So I think that really showing us this mechanism helps us understand and appreciate the power of those cells. What do you think?

Dr Marie-Pier Tetreault: I absolutely agree, especially because in the clinic, what people need to remember is that what we get in terms of biopsy is most of, especially in adults, only epithelial cells. And so it's very important if we want to be able to translate to human disease, to really look in terms of signaling what's happening there. And for us to see how central it is, it's really encouraging to us, but will really help us to bring this to the clinic even faster. And with the collaborations with the great clinicians that we have and engineers, and taking to the next level with these new technologies, such as single cell RNA sequencing, we really believe that that's the first step to be able to bridge those gaps between the clinic and really find better therapeutics so that we don't only treat the symptoms, but we really try to cure these diseases.

Dr Pam Peeke (Host): Well, also prevent them. Prevention here is huge. And you have a phenomenal group there to be able to work together as a team, to be able to see how to integrate this new technology into a day-to-day practice of medicine, which I find to be very, very exciting. So, what should be explored next? What do you see now that you've done this great work? What's your next step?

Dr Marie-Pier Tetreault: Directly from this study, definitely, we want to look more into what do neutrophils do in each context of different types of esophageal diseases. That's the first thing, but really look closely at IL-23. But as I mentioned, our lab took it to the next level and we really are able to look into specific diseases. One of which is eosinophilic esophogitis and really look into what IKK beta is doing in that context. So by making it even more specific disease by disease, we want to take the same approach. And as you mentioned, try to be able to find better biomarkers or better therapeutics for it. So this is where the lab is going.

And as I mentioned, we took it to the next level by getting into this new technology called single cell RNA sequencing, where we're going to really be able to get even more detail in understanding what's going on early on for each of these diseases that you mentioned at the beginning of the podcast, naming gastroesophageal reflux, esophageal cancer, the early stage of esophageal cancer, scleroderma and achalasia.

Dr Pam Peeke (Host): Excellent. And when do you see actually integrating this into the standard care that we have now for esophageal disease?

Dr Marie-Pier Tetreault: Depending on the disease. I think eosinophilic esophagitis, it's probably the disease that we're the closest to be able to integrate it. Research at the bench takes time. So I would imagine that it's still going to be a few years, because there's still a few more details to fine tune, but I'm pretty confident with the approach that we're taking and making sure also having access to patient samples, that we're going to be able to go faster compared to what we've been able to do. But in a few years, we should start being able to see changes in the clinic.

Dr Pam Peeke (Host): That's fantastic. This is very, very exciting. So congratulations on the publication of this wonderful research and to the fact that we have a promise now of new ways to be able to potentially prevent, if not cure, esophageal disease, all the way from inflammation to the detection of early signs of potential carcinoma.

So, again, kudos to you in your laboratory for developing this new methodology for integration into clinical practice. Do you have any last words of wisdom from the study that you want to impart to our clinicians who are listeners?

Dr Marie-Pier Tetreault: I mean, it's going to be the same message that I just mentioned. There's hope that now with multidisciplinary research, that really many aspects, the clinic, the bench are really looking more into taking care of these patients and really trying to find cures instead of just trying to work on their symptoms. So hang in there, it's coming.

Dr Pam Peeke (Host): There's a nice promise. Well, thank you so much, Dr. Tetreault. And to refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/gastro to get connected with one of our providers. Okay, that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians.

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