Engineers grow pancreatic organoids that can mimic real ones.
Pancreatic organelles. Studying this topic could help researchers to develop and test new treatments for pancreatic cancer, one of the deadliest cancers.
MIT engineers became partners with scientists at the Manchester Cancer Research Institute (in the UK) to develop a new way to grow tiny copies of the pancreas using healthy or cancerous pancreatic cells. These new models could help to develop and test potential medications for pancreatic cancer, which is currently one of the most difficult cancers to treat.
Using a special gel that mimics the extracellular environment surrounding the pancreas, the research team was able to grow pancreatic organelles allowing them to study important interactions between pancreatic tumors and their environment. Unlike some gels that are used for tissue growth, the new MIT gel is fully synthetic, easy to assemble, and can be produced with a consistent composition every time.
“Reproducibility is a major issue,” says Linda Griffith, the professor of pedagogical innovation at the School of Engineering and biological engineering and mechanical engineering professor. “The research community has been looking for ways to make more methodical cultures of these organelle species and to control the microenvironment.”
The researchers also showed that their new gel can be used to grow other types of tissue, including intestinal and endometrial tissue.
Griffith and Klaus Jorgensen, the team leader at the Manchester Institute for Cancer Research, UK, are senior authors of the paper, which is published in the journal “Nature Materials”. The lead author is Christopher Belov the PhD student at the Manchester Cancer Research Institute, UK.
Microenvironment simulation.
Traditionally laboratories have used commercially available tissue gel to grow organoids in laboratory glassware. But because the most widely used commercial gel is a complex mixture of proteins, proteoglycans and growth factors, it varies from batch to batch and contains unwanted components, says Griffith. It also does not always allow for multiple cell types to grow. About 10 years ago, Griffith’s lab began working on a synthetic gel that could be used to grow epithelial cells that form layers with other supporting cells.
The gel they developed is based on polyethylene glycol (PEG), a polymer that is often used for medical purposes because it does not interact with living cells. By studying the biochemical and biophysical properties of the extracellular matrix that surrounds organs in the body, the researchers were able to determine the features they could include in PEG gel to help cells grow in it.
Features of this method.
One of the key features is the presence of molecules called peptide ligands that interact with cell surface proteins called integrins. Adhesive bonding between ligands and integrins allows cells to attach to the gel and form organelles. The researchers found that incorporating small synthetic peptides derived from fibronectin and collagen into their gels allowed them to grow a variety of epithelial tissues, including intestinal tissue. They showed that supporting cells called stromal cells with immune cells can also thrive in this environment.
In the new study of Griffith and Jorgensen they wanted to see if the gel could be used to support the growth of normal pancreatic organelles and pancreatic tumors. It was difficult to grow pancreatic tissue in such a way as to reproduce both cancer cells and a supportive environment, because once the tumor cells of the pancreas are removed from the body, they lose their distinctive cancerous features.
Griffith’s lab developed a protocol for making the new gel and teamed up with Jorgensen’s lab, which studies pancreatic cancer biology for testing this protocol. Jorgensen and his students were able to produce a gel and use it to grow pancreatic organelles using healthy or cancerous pancreatic cells obtained from mice.
“We got the protocol from Linda, and we got the reagents, and then it just worked out,” says Jorgensen. “I think it says a lot about how reliable the system is and how easy it is to implement it in the laboratory.”
Other approaches they tried were too complex or did not replicate the microenvironment seen in living tissues, he said. Using this gel, Jorgensen’s lab was able to compare pancreatic organelles with tissues they examined in live mice, and they found out that tumor organelles express many of the same integrins pancreatic tumors has. Other types of cells that normally surround tumors, including macrophages (a type of immune cell) and fibroblasts (a type of supporting cells), can also grow in the microenvironment.
Pancreatic Organoids Based on Patients' Cells.
The researchers also showed that they can use their gel to grow organelles from patients pancreatic cancer cells. They believe it may also be useful for studying lung, colon, and other cancer types. Such systems can be used to analyze how potential anticancer medications affect tumors and their microenvironment.
Griffith also plans to use the gel to grow and study tissue from patients with endometriosis, a condition in which the tissue lining the uterus grows outside the uterus. This can lead to pain and sometimes infertility.
One of the advantages of the new gel is that it is completely synthetic and can be easily made in the laboratory by mixing certain precursors, including PEG and some polypeptides. Researchers have filed a patent for this technology and are now licensing it to a company that could make the gel a commercial product.
The study was funded by Cancer Research UK, Rosetrees Trust, the European Research Council Consolidator Award, the National Science Foundation, the National Institutes of Health and the Defense Advanced Research Projects Agency.
