Cancer cells produce small amounts of their own form of collagen, creating a unique extracellular matrix that affects the tumor microbiome and protects against immune responses, according to a new study by researchers at The University of Texas MD Anderson Cancer Center. This abnormal collagen structure is fundamentally different from normal collagen made in the human body, providing a highly specific target for therapeutic strategies.
This study, published today in Cancer Cell, builds upon previously published findings from the laboratory of Raghu Kalluri, M.D., Ph.D., chair of Cancer Biology and director of operations for the James P. Allison Institute, to bring a new understanding of the unique roles of collagen made by fibroblasts and by cancer cells.
“Cancer cells make an atypical collagen to create their own protective extracellular matrix that helps their proliferation and their ability to survive and repel T cells. It also changes the microbiome in a way that helps them thrive,” said Kalluri, senior author on the study. “Uncovering and understanding this unique adaptation can help us target more specific treatments to combat these effects.”
Type I collagen, the most abundant protein in the body, is produced by fibroblasts and found mostly in bones, tendons and skin. Previously, collagen in tumors was believed to promote cancer development, but Kalluri’s laboratory showed that it likely plays a protective role in suppressing pancreatic cancer progression.
In its normal form, collagen is a heterotrimer consisting of two α1 chains and one α2 chain, which assemble to form a triple-helix structure as part of the extracellular matrix. However, when studying human pancreatic cancer cell lines, the researchers discovered the cells expressed only the α1 gene (COL1a1), whereas fibroblasts expressed both genes.
Further analysis revealed that cancer cells have silenced the α2 gene (COL1a2) through epigenetic hypermethylation, resulting in a cancer-specific collagen ‘homotrimer’ made up of three α1 chains.
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