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 cellbuilds on previously published findings from the lab of Raghu Kalluri, MD, Ph.D., Chair of Cancer Biology and Chief Operating Officer of the James P. Allison Institute, to provide new understanding of the unique roles of collagen produced by fibroblasts and cancer cells.
Cancer cells make atypical collagen to create their own protective extracellular matrix that helps their proliferation and ability to survive and ward off T cells. It also changes the microbiome in ways that help them thrive. Discovering and understanding this unique adaptation can help us target more specific treatments to combat these effects.”
Raghu Kalluri, MD, Ph.D., lead study author
Type I collagen, the most abundant protein in the body, is produced by fibroblasts and is found primarily in bones, tendons, and skin. Previously, collagen in tumors was believed to promote cancer development, but Kalluri’s lab showed that it likely plays a protective role in suppressing pancreatic cancer progression.
In its normal form, collagen is a heterotrimer composed of two α1 chains and one α2 chain, which come together to form a triple helix structure as part of the extracellular matrix. However, when studying human pancreatic cancer cell lines, researchers found that the cells expressed only the α1 gene (COL1a1)while fibroblasts expressed both genes.
Further analysis revealed that the cancer cells silenced the α2 gene (COL1a2) by epigenetic hypermethylation, resulting in a cancer-specific collagen “homotrimer” composed of three α1 chains.
Loss of cancer-specific collagen reduces cancer progression and may boost anti-tumor immune response
To study the real effects of this observation, the researchers created knockout mouse models of pancreatic cancer with COL1a1 suppressed only in cancer cells. Loss of this cancer-specific homotrimer reduced cancer cell proliferation and reprogrammed the tumor microbiome. This led to lower immunosuppression, which was associated with increased T-cell infiltration and elimination of cancer cells.
Additionally, these knockout mice responded more favorably to anti-PD1 immunotherapy, suggesting that targeting this cancer-specific collagen may help boost the anti-tumor immune response.
“This finding illustrates the importance of mouse models, because it wasn’t until we noticed a difference in their survival that we discovered that this abnormal collagen variant existed and was produced specifically by cancer cells,” he said. Kaluri. “Because it is generated in such small amounts compared to normal collagen, the homotrimer would otherwise have gone unnoticed without specific tools to differentiate them.”
Cancer-specific collagen alters tumor microbiome and immune profile
Given the relationship between gut and tumor microbiomes and immune responses, the researchers also explored the microbiome in their mouse models. Interestingly, the loss of cancer-specific collagen led to changes in the bacterial composition of the tumor. There was a corresponding decrease in myeloid suppressor cells (MDSCs) and an increase in T cells, contributing to favorable survival outcomes.
These effects were completely reversed by disrupting the microbiome with antibiotics, suggesting that cancer-specific collagen promotes cancer progression by enhancing a tumor-promoting microbiome. This is the first evidence that the extracellular matrix directly influences the tumor microbiome, which could help researchers understand how cancer cells have evolved these adaptations against an immune response.
Further investigation clarified some of the mechanisms behind these findings, demonstrating that loss of cancer-specific collagen increased levels of CXCL16, which attracts T cells, and reduced expression of CXCL5, which attracts MDSCs. . The loss of the collagen homotrimer also increased the amount of normal fibroblastic collagen in the stroma, which Kalluri’s lab showed inhibits tumor progression. These results provide further evidence that cancer-produced homotrimers affect signaling pathways that can alter the tumor immune profile.
Cancer-specific collagen and its receptors represent new therapeutic targets
The study also found that abnormal collagen upregulates signaling pathways associated with cancer cell proliferation by binding to a surface protein called integrin α3. Indeed, suppression of integrin α3 live increased T-cell infiltration and prolonged survival, highlighting this interaction as a very specific target for potential therapeutic strategies.
“No other cells in the normal human body make this unique collagen, so it offers enormous potential for the development of highly specific therapies that can improve patient responses to treatment,” Kalluri said. “On many levels, this is a fundamental discovery and an excellent example of how basic science uncovers important discoveries that could ultimately benefit our patients.
While the current study looked specifically at pancreatic cancer, Kalluri noted that collagen homotrimers are also seen in other cancer types, including lung and colon cancers, signifying a possible unifying principle. with broad implications for cancer treatment.