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In collaboration with Cancer Research UK Manchester Institute scientists, engineers from MIT have created a new method to create tiny replicas of pancreas using healthy and cancerous pancreatic cell lines. These models could be used by researchers to test and develop potential treatments for pancreatic cancer. This is one of the most difficult types.
Researchers were able to create pancreatic organoids using a gel that replicated the extracellular environment of the pancreas. This allowed them to study the interactions between pancreatic cancers and their environment. The new MIT gel, unlike other gels used to grow tissues, is entirely synthetic and easy to assemble. It can also be made with a consistent composition every single time.
The issue of reproducibility is a major one. The research community has been looking for ways to do more methodical cultures of these kinds of organoids, and especially to control the microenvironment.”Linda Griffith, the School of Engineering Professor of Teaching Innovation and a professor of biological engineering and mechanical engineering
The issue of reproducibility is a major one. The research community has been looking for ways to do more methodical cultures of these kinds of organoids, and especially to control the microenvironment.”
Linda Griffith, the School of Engineering Professor of Teaching Innovation and a professor of biological engineering and mechanical engineering
Researchers also demonstrated that the gel could be used to grow other types tissue, such as intestinal tissue and endometrium tissue.
Senior authors of the paper are Claus Jorgensen and Griffith, a group leader from the Cancer Research UK Manchester Institute. Christopher Below is the lead author. He was a graduate student at Cancer Research UK Manchester Institute.
Simulating the microenvironment To grow organoids in a laboratory dish, labs used tissue-derived gel. Griffith states that the most popular commercial gel is a complex mixture protein, proteoglycans and growth factors. It is not always suitable for all applications and may contain undesirable components. It doesn’t allow for the growth of different types of cells. Griffith’s lab began work 10 years ago on a synthetic gel to be used for growing epithelial cells. These cells form the sheets that line most of the organs.
They developed a gel based on polyethylene gall (PEG) which is a polymer that doesn’t react with living cells. The researchers studied the biochemical and biophysical characteristics of the extracellular matrix that surrounds organs within the body to determine features they could add to the PEG gel to aid in cell growth.
One of the key features is the presence peptide-ligand molecules, which interact with integrins and cell surface proteins. Sticky binding between integrins and ligands allows cells to stick to the gel, forming organoids. Researchers discovered that small amounts of synthetic peptides from collagen and fibronectin could be used to create epithelial tissue, including intestinal tissue. These researchers also found that stromal cells and immune cells can thrive in this environment.
Griffith and Jorgensen wanted the gel to be used in the support of the growth of normal and malignant pancreatic organoids. It has been difficult in the past to grow pancreatic tissue that mimics the environment and cancerous cells.
Griffith’s laboratory developed a protocol for producing the new gel. The lab then collaborated with Jorgensen’s laboratory, which studies the biology and treatment of pancreatic cancer. Jorgensen’s students were able produce the gel using pancreatic organoids grown from pancreatic cancerous or healthy pancreatic cells taken from mice.
Jorgensen states, “We received the protocol from Linda. We also got the reagents into the system and it worked.” This speaks volumes about how robust and easy the system is to use in the lab.
He says that other approaches they tried were too complex or didn’t replicate the microenvironment in living tissue. Jorgensen’s laboratory was able to use this gel to compare pancreatic organoids with tissues from living mice. They found that tumor organoids expressed many of the same integrins as pancreatic cancers. Other types of cells that surround tumors, such as macrophages (an immune cell type) and fibroblasts(a support cell type), were also able grow in this microenvironment.
Cells derived from patients Researchers also demonstrated that their gel can be used to grow organoids using pancreatic cancer cells taken from patients. It could be used to study colorectal and lung cancers. These systems could be used for analyzing how potential cancer drugs impact tumors and the microenvironment.
Griffith plans to also use the gel to study and grow tissue from endometriosis patients. This is a condition where the tissue that lines your uterus grows outside of the uterus. This can cause pain, and sometimes even infertility.
The new gel has many advantages. It is entirely synthetic and can be easily made in a laboratory by mixing specific precursors such as PEG with some polypeptides. Researchers have filed a patent for the technology and are now licensing it to a company who could commercially produce the gel.
Massachusetts Institute of Technology
Below, C.R., et al. (2021) A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. Nature Materials. doi.org/10.1038/s41563-021-01085-1.