00:00:00: A very warm welcome to our podcast series, reporting from UEG Week, twenty twenty-five in Berlin.

00:00:09: And I hope that you are full of memories.

00:00:12: My name is Julia Meijerle.

00:00:14: And it's my great pleasure today in my capacity as the previous chairman of the scientific committee and in charge of organizing the UEG program for last year.

00:00:28: to interview today Francisco X Real, who is one of the co-directors for our novel format, the Digestive Disease Mechanism Summit, which we held for the first time in Berlin.

00:00:45: Haco is a professor of cell biology.

00:00:48: He's the director of the tumor biology program at CNIO, the Spanish Cancer Institute.

00:00:56: And his previous work mainly focused on the transcriptional interaction between carcinogenesis and inflammation.

00:01:07: And currently, he works on precision prevention.

00:01:11: So I think Paco and myself would start outlining why both of us are strong believers that the digestive disease mechanism summit is an important add-on to the ever-increasing and ever-getting more popular program of UEG Week.

00:01:32: Paco, tell our audience why you as a basic scientist believe that the DDM was a success.

00:01:40: Thank you, Julia.

00:01:41: Thank you, the board of the UEG, for considering the possibility of setting up.

00:01:47: a workshop like the DDM Summit.

00:01:50: This is a really unique fact because I'm not aware of any other large society in Europe or even in the US that has set up this kind of meeting inspired in many ways by the Gordon conferences of the EMBO workshops.

00:02:04: There is evidently a great increase in complexity and depth regarding the mechanisms, molecular and cellular mechanisms that are fundamental for cell biology and for understanding organisms that are happening in the last decades.

00:02:19: And there is an increasing need to translate the depth of this knowledge into the clinical arena.

00:02:25: And we first have to make this knowledge available in an easy manner to physicians and to actually recruit the best physicians to become, physician scientists to become interested in the basic mechanisms of disease.

00:02:39: On this occasion we decided to focus on cancer because it's just such a broad and important issue from a clinical standpoint and medical standpoint also because many things are happening these days in the cancer arena that merit consideration and we decided to focus on three of the major cancers of the GA tract, colorectal, pancreatic and liver cancer.

00:03:00: We did so because I think they represent a broad spectrum of biology of what happens in the GI field, with the colon and the tube being a type of tissue where there is constant renewal, the liver being a tissue where there is potential for renewal, but normally the tissue is quiescent, and the pancreas is a tissue where there is normal quiescence and actually the potential for regeneration is much lower.

00:03:26: So actually we have three cell biology scenarios that are very distinct and that provide different opportunities for learning about the mechanisms involved in disease.

00:03:35: Yeah and I think the program was really excellent and I have to give credit to the three course directors to be honest.

00:03:44: So that's going to be you and there was also Matthias Heikenwelle and Maria Sibylja because you made it possible, the three of you.

00:03:52: that we had the highly scientist researchers as speakers at the DDM summit and at least my postdocs and researchers and collaborators who attended told me that the quality of the talks was outstanding and that they never had the opportunity to meet so many great researchers and learn so many things in depth than when they actually travelled to Berlin.

00:04:19: And that was something which was totally novel.

00:04:22: for me because usually all the researchers in my basic science lab declined to join me to Ouija Week because they always said there's nobody I can discuss my things with.

00:04:33: and that has totally changed.

00:04:35: And you mentioned that it's important that the best clinicians become clinician scientists, but I also believe that those who are not as deeply involved in science should understand the language of science and should be able to see the rapid progress and influence science by giving ideas of where the project should be driven to when it comes to treatment, prevention.

00:05:06: So when there is the need to ask a relevant clinical question and medical question that could be discussed with a basic scientist who would be much better suited.

00:05:18: to actually come up with a model system to test a hypothesis, which the clinician might not be able to do, but the clinician being able to come up with a testable hypothesis.

00:05:33: And I think the benefit of the exchange of ideas and the exchange of knowledge and methodology is of utmost importance if We want to be competitive in the field of gastroenterology and GI disease, GI cancer, when it comes to developing cures for our patient and improve patient care.

00:05:59: I completely agree with you.

00:06:00: We are extremely lucky that we got some of the best scientists, many of them from Europe, but we had excellent scientists, outstanding scientists coming from the US and from Asia.

00:06:11: I think that a global aspect of the DDM organization and of the DDM attendance was also crucial for its success.

00:06:20: I may want to start by giving some tips about some of the presentations and some of the topics that were covered that I think may provide opportunities for translation and that come from very basic research.

00:06:32: For example, I was particularly excited to hear Trevor Graham presentation about ulcerative colitis progression to colorectal cancer and his group and Many of the groups have extensively studied the genomic alterations present in preneoplasia associated with ulcerative colitis, but Trevor has taken a very deep approach to characterize non-displastic regions in the colonic mucosa of patients with ulcerative colitis to actually demonstrate that some of the histologically non-displastic regions do contain genomic aberrations, including aneuploidy, that can be tracked for clonal selection.

00:07:11: and that can predict the risk of developing neoplasia, providing a map of how the evolution from the occurrence of mutations and an oploidy in apparently normal tissues can progress or can lead the progression to the development of colorectal cancer with a clear impact on early detection or on risk prediction.

00:07:32: So this is one, for example, of the highlights where I think that the basic genomics can contribute greatly to improved patient care.

00:07:38: Yeah, and that is especially the case if you think about that whenever we find just a dysplasia somewhere that will result in complete colactomy.

00:07:49: So if we have some risk stratification, we could probably help our patients in keeping their colon for a longer time, which increases quality of life.

00:08:00: So I think these basic signs directly affects our clinical care and therefore it's important that we learn about it and learn about the possibilities.

00:08:12: Completely agree, completely agree.

00:08:14: In the area of colorectal cancer we were also extremely lucky that we had Eduard Ballet from Barcelona who has done a fantastic work in various areas of stem cell biology.

00:08:25: in colorectal cancer.

00:08:27: And after his quite seminal work on the role of TGF-beta receptor signaling in the maintenance of persistent cells in these tumors, he presented some novel and published work on the role of SPP-I or steopontine I expressing microphages at modulators of the TGF-beta signaling.

00:08:46: And I think that this was one of the highlights of the presentation as well.

00:08:51: And it actually provides opportunities of identifying novel molecules that until now actually there have been recent reports pointing to SPP-I also in pancreatic cancer.

00:09:01: So I think that together this recent work in pancreas and colorectal cancer clearly points to SPP-I as a novel potential target of a very different cell type, since this is an extracellular matrix protein.

00:09:15: And I think that that was also one of the highlights for me about the meeting.

00:09:18: Do you think the stroma and the tissue microenvironment is a friend or foe?

00:09:23: Do you think we will learn from that?

00:09:26: We've learned over the last years that the role of the stroma is very context dependent.

00:09:30: We cannot just talk about it being friend or foe.

00:09:34: It depends on the context, it depends on the stage of the disease, preneoplastic conditions versus the tumor, very early stages of clonal selection.

00:09:43: I think we need to learn a lot about that.

00:09:46: But definitely what it's bringing up is some significant targets that need to be explored.

00:09:51: And I'm not sure that the paradigm targeting strategies that we have for other types of proteins can be followed when considering the stroma.

00:09:59: But definitely I think what it also points out is that the main culprits and the main targets that we need to tackle.

00:10:07: They may not necessarily always be at the level of the tumor cell.

00:10:10: They actually can come from other cells.

00:10:12: In this case, the microfaces.

00:10:13: So to me, one of the talks which I really enjoyed a lot, and I can clearly tell you upfront why, was the talk by Andreas Trumpe, when he actually showed us how he characterized single neurons and showed that they were reprogrammed in pancreatic cancer.

00:10:33: And the reason why I was so fascinated, because around UEG Week, I was contacted by Patrick Michel, who is the chairman of gastroenterology and hepatology.

00:10:44: at the University of Heidelberg and has a very strong interest in pancreatic cancer, suggesting that we should set up a trial where we would do in a neoadjuvant setting would apply twenty-five grays to the celiac plexus.

00:11:02: So, denervating the pancreas together with a neoadjuvant chemotherapy and then see whether that in on the long term could result in a reprogramming of the tumor microenvironment and increase survival after resection.

00:11:20: And that showed that a nature paper by Andreas Trump, which was only published in April, can now already be translated into a hypothesis which can be tested in a clinical trial.

00:11:34: This really showed me how big the interaction is between a clinician and a higher ranked basic science and we all understood how nature publications evolve.

00:11:48: Everything we find in nature, nature.

00:11:52: So if we look around the window, be it astronomy, be it biology, whatever be it medicine, which is of great importance, you will find published in nature.

00:12:05: And if we can already translate it in a clinical testable hypothesis, I think that is something which is really fascinating to me.

00:12:13: So I believe that understanding the neural network and the peripheral nervous system in pancreatic cancer might really be a new therapeutic angle.

00:12:23: I completely agree and I think the seminal work that Andreas has performed both conceptually, although the concept of the interaction between nerves and tumor cells in pancreatic cancer is relatively old.

00:12:35: And we have many people at UEG who have contributed to the field in the past.

00:12:39: But I think that what Andreas has brought in is the state of the art, the most state of the art technology, as well as a fresh view on the topic.

00:12:50: And I think that the transition to a clinical trial, which he presented the details of during the meeting, is really a fantastic achievement within this short period of time.

00:13:01: And it just means that we have to have the people who can run the trials and the people who can run the science meet in a way that they can effectively communicate to accelerate this translation.

00:13:12: But that's a fantastic example, completely agree.

00:13:15: So what's your take on... the current challenges of KRAS targeting?

00:13:21: I think the beauty of the current landscape is that KRAS, which we are very rapidly beginning to understand both the potential and when and the limitations as a target, I think KRAS is evolving from being a signaling target for therapy to moving a hub that not only controls proliferation and differentiation in tumor cells, but has a major impact on the immune microenvironment.

00:13:50: So actually, I think what we're learning and this was very well presented and discussed at the meeting by several people, but very particularly, I think, by Thomas Tamela from Memorial Sloan Kettering, is that targeting KRAS has a major impact on plasticity.

00:14:07: Plasticity is very highly connected to the microenvironment, including the immune microenvironment, and that remodeling the microenvironment through manipulation of KRAS activity will actually open a scenario where we will be dealing with the potential of combining targeted therapies not only possibly with chemotherapy as was pretty obvious from what we know already in pancreatic cancer but also with immune checkpoint locates or other immune manipulations including vaccines.

00:14:37: So I think this is the the the crowding of all these fields emerging in a way I think makes it extremely interesting with great potential and actually provides opportunities for overcoming some of the therapy-specific resistance mechanisms that are very challenging in cancer?

00:14:54: No, I agree.

00:14:55: And I think there were also novel mechanisms presented how you could actually get a synergistic effect of K-RAS inhibition with other drugs.

00:15:05: And I found that really interesting.

00:15:06: And one topic which I found also really interesting was the role of neutrophils in pancreatic cancer outlined by Dieter Sauer.

00:15:18: Because so far, to me, neutrophils were always the first line defense for bacteria in infection and mainly played a role in removing abscesses.

00:15:29: But here he clearly showed that they have a strong influence on metastasis formation.

00:15:34: And I think, again, that might be a novel target which has been previously overlooked.

00:15:39: Yeah, I completely agree.

00:15:41: Details work on neutrophils opens great possibilities, especially because neutrophil was considered the dumb cell, so to say, in the cancer field.

00:15:49: Not in infection, but yes, in the cancer field.

00:15:52: But maybe before we close, let's talk... a cap one minute about liver, because I think some of the work that was presented in liver we didn't talk about that is really very interesting and striking.

00:16:03: And in addition to the fact that there was a presentation by Tombert from Edinburgh about the development of a range of novel mouse models of liver cancer, which we have been in need for, was really outstanding.

00:16:16: But I'd like to highlight briefly the work of Suchira Gallage of Guadalupe Savio from CNIO, both of whom emphasized the relevance of metabolism as a critical driver and also target in liver cancer and probably also in other cancers.

00:16:33: Suchira showed the critical potential of intermittent fasting in mass and liver cancer and the potential to use intermittent fasting as a strategy to identify targets that could be dealt pharmacologically without the need of the fasting.

00:16:49: And he pointed the relevance of Piper Alpha and PCK-I.

00:16:53: And I think this is opening new areas both, as I said, in the premium plastic and tumor scenario.

00:17:00: And while Lupe Sabio presented some of her very recent work on P-Thirty-Eight MAP kinase as a regulator of the immune response, and in particularly CDA positive T cells.

00:17:12: So I think that we are seeing the emergence in several tumor types of these functional interactions between signaling, map kinase, root signaling, for example, immune mechanisms and metabolic mechanisms, which really I think will change in the next few years the potential to manipulate both the pre-neoplastic and the neoplastic processes in themselves.

00:17:37: So one thing I would like to mention before we're going to give you an outlook on next year is we have now been talking a lot about the invited speaker panel and that was really outstanding.

00:17:48: However, the liveliest part of the whole meeting was the poster discussion.

00:17:54: And I really enjoyed it that we had these poster runs and that all the more than a hundred and eighty participants who submitted their abstracts gave a flash talk, a one-minute flash talk inside the sessions and then stand next to their poster.

00:18:10: And there was a lot of interaction and also collaborations which have been started.

00:18:15: There's emailing back and forth between the different groups which presented their work at UEG and I found this platform of exchange and The establishment of novel collaborations, a really huge asset, which I enjoyed a lot to see.

00:18:32: So you're not only traveling to Ouija and the DDM Summit because you want to listen to these high-ranked researchers, but you should definitely come there next year if you want to discuss with your colleagues and your peers, find people working in the same field with the same depth of interest.

00:18:53: in moving forward a basic science or medical science project.

00:19:00: Can you agree on that Pako?

00:19:01: Completely agree and I have to say to start with... and emphasize that UEG was extremely supportive of the attendance of young people to the DDM.

00:19:12: This was the basis for having a fantastic set of posters, and we had dedicated much more time for poster discussion than in any other meeting I have recently been to, except for possibly the Gordon conferences.

00:19:25: And this is essential, I think, for the success of DDM in future occasions.

00:19:30: I agree, and we will keep this strategy.

00:19:34: So what we're going to do next year?

00:19:37: What do you think, Paco?

00:19:38: What would you suggest?

00:19:40: Should we continue?

00:19:41: Well, definitely we have to continue.

00:19:43: I think we have to build the DDM as a standard for the UEG meeting.

00:19:48: This takes time.

00:19:49: We have to understand that to consolidate this will take time.

00:19:53: I think that we realize that by focusing on cancer, We are actually bringing in other aspects, which are not necessarily the main cancer stream, but sort of adjacent, inflammation, metabolism, et cetera.

00:20:06: But I think that maybe if we now focus in the next occasion on inflammation, we will actually have cancer and other aspects coming in so collateral.

00:20:16: And I think that the problem of inflammation in GI diseases is so essential.

00:20:21: And it is also so critical for other diseases like cancer that this might be a good idea for the next DDM summit.

00:20:28: Yeah, I think it will be very nice to think about what is fibrosis in GI disease?

00:20:35: Is this scarring?

00:20:36: Is this a metabolic active, say, tissue?

00:20:40: How does it reflect the disease?

00:20:43: And I'm sure that we will find with our new course directors, which we are currently speaking to, we will establish an equally interesting faculty and we hope that we can even attract more young researchers from all of the basic science labs from all over Europe and maybe not only Europe.

00:21:02: I mean, we learned that the fifth highest number of participants at Ouija came from Northern America.

00:21:09: So maybe we could even claim that we would like to see all the young researchers worldwide to participate.

00:21:16: in the DDM Summit next year in Barcelona and I'm sure we will provide you a perfect program but we will also provide you with a wonderful environment allowing for networking and interaction and great social activities like we had our DDM Summit dimna and like the UIG night which was a party dating back to the twenties and I still have wonderful pictures and photographs from Paco and my colleagues.

00:21:47: Paco, thank you very much for taking the time out of your very busy schedule.

00:21:51: And more important, thank you very much for... contributing so much time and devoting so much effort into setting up this DDM format.

00:22:00: I mean the GI community is really grateful that you have undertaken this endeavor and I hope to see you at Ouija Week not only next year but from this year on ever.

00:22:12: Thank you, Julia.

00:22:13: And I would like to take this opportunity to thank Matthias and Maria for contributing to building this great program and to all the attendees and speakers for making it a success for UIG.

00:22:25: Thank you for listening to our podcast.

00:22:27: I hope you enjoyed it.

00:22:28: And if you have any more questions, don't hesitate to contact either Paco or myself.

00:22:34: Thank you very much.

00:22:35: Bye, all.