Newly published research using genetically engineered mice models (GEMMs) has shown that pancreatic cancer cells produce a unique form of collagen (Col1) that helps protect them from attack by the immune system, promotes their proliferation, and alters the surrounding microbiome.
The study, which builds on previous work conducted by researchers at The University of Texas MD Anderson Cancer Center, could open new avenues to potential therapeutic targets for pancreatic ductal carcinoma (PDAC). PDAC is a type of cancer that develops from the duct cells lining the pancreas. It is currently the seventh leading cause of cancer deaths, with over 450,000 people dying worldwide each year. Because of this, understanding the biochemistry and molecular biology behind PDAC’s Col1 variant has never been more important.
Collagen I Variant in Pancreatic Cancer
To uncover the reason behind the variation seen in PDAC Col1, the authors used a methylation analysis of PDAC cell lines against a database of cancer cell lines. In healthy cells, they found that Col1 exists as a heterotrimer, with the COL1A1 and COL1A2 genes encoding the proteins making up the functional Col1. However, in most of the PDAC cell lines, the COL1A2 gene was hypermethylated at its promoter region, suppressing it. This meant its Col1 was only made up of the COL1A1 encoding protein, forming a homotrimer instead.
The effect of this variation was found to be significant. RNA sequencing revealed that the Col1 variant upregulated multiple pathways that promote cancer growth at the transcriptional level. It also affected the tumour microbiome, leading to more advanced tumour progression.
Collagen I Knockouts in Pancreatic Cancer
To study the impact of this Col1 variant more closely, the researchers decided to create knockout mice models to see how well the pancreatic cancer survived without it.
They found that mice with the COL1A1 gene deleted in their cancer cells (which prevents formation of the unique Col1 homotrimer) survived an average of 30 days longer than healthy controls. Why? It appears that in normal circumstances, Col1 forms a protective bubble around cancer cells in the form of an extracellular matrix, aiding their proliferation and allowing them to repel T cells.
Intriguingly, the knockout mice also seemed to present with an altered microbiome which corresponded with a decrease in myeloid-derived suppressor cells and an increase in T cells. This would suggest Col1 is able to promote cancer proliferation by creating a microbiome that is favourable to the cancer.
Therapeutic Potential
During their research, the team also elucidated several potential mechanisms behind their findings – this included Col1 seemingly binding to a surface protein, integrin α3, to upregulate cancer proliferation pathways. Because Col1 has a different structure to that made by healthy human cells, it could offer researchers a highly specific target for future therapeutic strategies.
