Clare Kenyon
A new study shows that pancreatic cancer cells make a collagen which protects the tumour and changes the tumour’s microbiome, helping it thrive. Since this type of collagen is only produced by cancerous cells – and nowhere else in the body – the discovery holds exciting potential as a target for future cancer therapies.
Collagen is perhaps best known as the latest you-can’t-live-without-this supplement almost literally pushed down throats by the health and beauty industry. These pills, injections and powders tend to be associated with improving skin elasticity and health, but in the body collagen is the most abundant protein and is found in bones, tendons and, of course, skin. This type of collagen, Type I collagen, is produced by special cells found in connective tissue called fibroblasts.
Previously, Type I collagen in tumours was thought to promote cancer development, but studies by by Dr. Raghu Kalluri at the University of Texas MD Anderson Cancer Center have demonstrated that in fact, Type I collagen produced by cancer-associated fibroblasts actually suppresses pancreatic cancer progression.
Now, a research group led by Kalluri has discovered that pancreatic cancer cells actually produce a special type of collagen – called homotrimer – that is different from the ubiquitous Type I collagen. Type I collagen is made up of three chains of material (two chains of α1 collagen and a chain of α2 collagen) which form a helix structure as part of what is known as the extracellular matrix.
“The extracellular matrix is kind of like a jungle gym or a 3D spiders’ web”, explains Dr. Jessica Buck, a cancer researcher at Telethon Kids Institute and University of Western Australia. “Changing the type and structure of the web can sometimes make it more difficult for immune cells to squeeze through the web and into the tumour”.
Kalluri’s research has shown that cancer cells silence the gene that produces the α2 chain, making its homotrimer collagen out of three α1 chains instead. This fundamentally changes the extracellular matrix, enabling the tumour to protect itself from the body’s immune system and repel invasion by T-cells. “There are many different types of T-cells, but their most important function is to detect and kill infected and abnormal cells,” says Buck.
The study also found evidence that the homotrimer is able to influence the environment within the tumour, making the microbiome more favourable for cell proliferation. This suggests that the extracellular matrix can directly influence the tumour microbiome, giving researchers insight into how cancer cells have adapted to evade the body’s immune response.
Finally, Kalluri and team used mouse models where the gene responsible for the α1 chain had been deleted in the cancer cells. These models showed reduced cancer cell population growth, and a less-favourable tumour microbiome, leading to increased T-cell infiltration and elimination of the cancer cells. These mice responded more favourably to anti-PD1 immunotherapy – a treatment already in use – suggesting a more effective cancer treatment approach.
Kalluri’s research focussed on pancreatic cancer cells, but this unique cancer collagen has also been found in lung and colon cancer. “In fact, at this point we have not found a tumour-type that does not generate homotrimer”, he says.
According to Buck, “pancreatic cancer is a very deadly cancer. The five year survival rate is only 11% [meaning that 89% of people will die within 5 years of their diagnosis]”.
Survival rates for lung cancer can be as low as 7%, while colon cancer can vary widely (depending on when it is detected), ranging from 14% to 91%. As Dr. Frederic Sierro, an immune system researcher at Australia’s Nuclear Science and Technology Organisation (ANSTO), notes, “in the case of pancreatic cancer, any improvement on these dismal statistics would make a large difference”.
This study is a “discovery science study”, which according to Buck, means that it’s still very early stages. From here, it’s “generally five years or so to go from mice to first-in-human testing, and decades to go from studies in mice to widespread clinical use”. So, it won’t be an overnight miracle cure, but as Kalluri explains, “no other cell in the normal human body makes this unique collagen, so it offers tremendous potential for the development of highly specific therapies … On many levels, this is a fundamental discovery and a prime example of how basic science unravels important findings that could later benefit our patients.”