In this interview, News-Medical speaks with Linxiang Lan, a staff scientist at the Cancer Research Institute and lead author of an article presenting a key discovery that could pave the way for new treatments for pancreatic cancer. .
Can you please introduce yourself, tell us about your scientific training and what inspired your latest research?
I am a staff scientist from the Cancer Stem Cell Laboratory at the London Cancer Research Institute. I did my PhD. at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, from 2009 to 2013. During my PhD, I worked on breast cancer, focusing specifically on the signaling pathways that control the development and progression of breast cancer. . I then joined Professor Axel Behrens ’lab at the Francis Crick Institute as a postdoctoral fellow in 2016 and began working on pancreatic cancer.
In 2020, our lab moved to the Cancer Research Institute (ICR) in London and I became a staff scientist. My main scientific interest is the biology of cancer. Specifically, I am very curious about certain questions: when and how do cancer cells acquire aggressive properties and how do they spread throughout the body? We know that the spread of cancer cells is one of the leading causes of death in cancer patients, including those with pancreatic cancer.
Pancreatic cancer has the lowest survival rates of common cancers. Can you tell us a little bit about the epidemiology of pancreatic cancer and the treatment options that currently exist?
Pancreatic cancer is known for its high mortality rate. In the UK, the survival rate is around 7%, meaning only 7% of pancreatic patients will survive for five years or more. Every year in the UK around 10,000 people are diagnosed with pancreatic cancer, and more than 9,000 patients die from it. Currently, pancreatic cancer is the fifth leading cause of cancer-related deaths in the country.
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Currently available treatments include surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. But these last two therapies are only used in a very small group of patients. We know that pancreatic cancer is often diagnosed in advanced stages. This means that many patients cannot undergo surgery when they are diagnosed.
The main problems with these therapies, including chemotherapy and radiation therapy, are resistance and relapse, which means the cancer often returns after therapy. In addition, these therapies have quite considerable toxicity and side effects. Therefore, the development of new therapies, including targeted therapies, is urgent for pancreatic cancer.
Prior to your study, what was known about the spread of pancreatic cancer cells and, most importantly, what was not known?
We know that the spread of cancer cells is one of the leading causes of cancer death in many types of cancer, including pancreatic cancer. Much effort has been made to study why and how cancer cells spread. But still, the mechanism behind this was largely unknown. For example, many scientists have tried to identify genes that control metastatic spread. But so far, very few unique genes have been found. Previously, many studies have shown that pancreatic cancer is not uniform, but often contains different populations of cancer cells.
For example, many pancreatic cancers contain different types of epithelial and mesenchymal cancer cells. Epithelial cell types are often found in cancer in the early stages, while mesenchymal cancer cell types often become more numerous as the tumor progresses. It is also known that mesenchymal cancer cell types tend to be more aggressive and have certain properties that allow them to spread more easily throughout the body.
Some studies have shown that epithelial cell types and mesenchymal cell types can be converted to each other within a pancreatic tumor, but it was not known how this conversion occurs and whether cancer cell types epithelial and mesenchymal cell types communicate with each other. That is why we were focusing on this question and aimed to understand the functions of these different populations of cancer cells in the spread of pancreatic cancer.
Tell us how you conducted your research and what were your main findings?
We used two models; genetic mouse models for pancreatic cancer and mini tumors, also called organoids. After turning off a gene encoding a protein called GREM1, we found that most epithelial cancer cell types became mesenchymal cancer types, which are much more aggressive and invasive. We also found that this rapid change from epithelial cancer cells to mesenchymal cancer cells caused a dramatic increase in the spread of cancer cells to other parts of the body.
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For example, in 90% of mice with GREM1 elimination, the cancer spread to the liver. In contrast, in normally functioning GREM1 mice, only 15% of cancers spread to the liver. In organoids, we also observed that turning off GREM1 caused cancer cells to change from epithelial to mesenchymal types. What is more interesting is that when we increased GREM1 to a high level, we found that high-level GREM1 can reverse mesenchymal cells to epithelial cells. Therefore, this means that a high level of GREM1 can reverse very aggressive cancer cell types to a less aggressive form. This is surprising because this suggests that GREM1 may have therapeutic value for returning malignant cells to less aggressive cells.
In your study, you used “mini-tumors” or organoids. What benefits do they offer in cancer research?
Recently, organoids have become increasingly popular in biomedical research, and tumor organoids are widely used in cancer research. There are quite a few advantages for organoid models in cancer research. For example, compared to mouse models, such as tumors in mice transplanted from samples from human patients, the generation of tumor organoids is much faster. We can usually generate organoids derived from the patient in a month or two. Transplant tumors in mice usually take much longer.
Second, tumor organoids have been shown to have the ability to preserve or maintain the diversity of cancer cells, as seen in primary human cancers. For example, in our organoid models, we found that both epithelial and mesenchymal cancer cells can be captured. In contrast, traditional 2D cell culture conditions are quite selective. This means that they select only certain types of populations and therefore diversity is lost.
Organoids are also more stable compared to traditional 2D dish cultures. Many studies have shown that organoids maintain their properties without major changes after long-term cultivation. Therefore, this makes the search much more convenient.
The study found that the cell pattern of pancreatic tumors follows a mathematical law. What is this law and what does it mean to understand pancreatic cancer?
This law is the Turing model for biological tissue modeling. This model was proposed by Alan Turing over 70 years ago. He proposed that two individual chemicals that interact with each other can control tissue or organ patterns. The Turing model is found throughout nature: it governs the pattern of a leopard’s spots and the skin patterns of a balloon fish. In our study, we found that mesenchymal cancer cells can produce a protein called BMP2, and BMP2 is important for keeping this type of cancer cell in a mesenchymal state.
Surprisingly, we found that in mesenchymal cancer cells, BMP2 induces the production of GREM1 and GREM1 is known as a BMP-2 inhibitor. Therefore, this means that BMP2 is produced in these cells, which then triggers the production of GREM1 and GREM1, in turn, decreases BMP2 activity. It’s kind of a negative feedback loop. This negative feedback loop especially affects the “fate” of epithelial cancer cells.
We believe that this interaction between BMP2 and GREM1 follows the Turing model. We propose that pancreatic cancer also follows this model to establish different epithelial and mesenchymal populations. But we need to work harder to validate whether other cancers also follow this model to establish the diversity of cell populations and the pattern.
How do you expect your findings to influence the future of pancreatic cancer treatment?
It is amazing that we have found that high levels of GREM1 can reverse mesenchymal cancer cells, which are very aggressive and more easily transmitted, to epithelial cells, which are less aggressive and more indolent. We believe that this knowledge can help us find a way to reverse aggressive cancer cells to less aggressive ones and therefore make tumors much more treatable with standard therapy. We believe that the signaling pathways involved in this process could present important therapeutic targets.
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What’s next for you and your research?
I am continually fascinated with research in our cancer stem cell lab led by Professor Axel Behrens. I want to work harder to better understand how cancer cells spread. For example, I would like to do some follow-up studies on GREM1 in different types of cancer to see if GREM1 controls the spread of other cancers. , My main ambition for the future is to help translate our knowledge of GREM1 and BMP2 into controlling the spread of pancreatic cancer to drug discovery so we can find new treatments for patients.
Where can readers find more information?
About Linxiang Lan
I am currently a staff scientist in the Cancer Stem Cell Laboratory of the Cancer Research Institute. I did my PhD. Water Birchmeier’s Lab at the Max-Delbrück-Center for Molecular Medicine from 2009 to 2013, and joined Prof. Axel Behrens Lab of the Francis Crick Institute for postdoctoral training in 2016, supported by two scholarships from DFG and German Cancer Aid. . I became a staff scientist after the lab moved to the …