Bacteria within the tumour microbiome can adapt to produce nutrients that allow cancer cells to resist treatment, researchers have found.Credit: Kateryna Kon/ Science Photo Library/ Getty Images
Unlike the usual energy-release pathways in normal cells, cancer cells are known to adapt to derive more energy from glucose uptake, followed by lactic acid fermentation — the so-called Warburg effect.
Now, a team at The University of Texas MD Anderson Cancer Center has made a game-changing discovery. In a paper published in Cancer Cell, they describe how lactic acid, or lactate, produced by bacteria in and around the tumour microbiome can also fuel tumour growth. The presence of the bacterium Lactobacillus iners (L. iners) causes metabolic rewiring or alterations in multiple metabolic pathways in cancer cells, resulting in resistance to radiation therapy.
“Our understanding of the tumour microbiome is growing,” says Lauren Colbert, a radiation oncologist at MD Anderson, and the paper’s co-author. “Our research shows that tumour-resident bacteria adapt as the tumour develops to produce what the cancerous cells need, and then feed off some of the nutrients that the tumour produces. This changes everything we know about metabolically targeting tumours.”
The team started looking into the association between L. iners and tumour radiation resistance during biomarker profiling of patients with cervical cancer. After eliminating other possible causes for increased chemoradiation resistance, such as immune response, they identified L. iners as strongly associated with outcomes and came up with the lactate hypothesis. In 101 patients with cervical cancer undergoing chemoradiation between September 2015 and March 2022, L. iners was found to be associated with poorer outcomes — both decreased recurrence-free survival (RFS) and overall survival (OS).
When the team then carried out targeted culture of L. iners from patient samples, they discovered the efficiency of the lactate-producing machinery. The researchers were able to induce treatment resistance by treating cancer cells in vitro with L. iners supernatant, which rewired the tumour cell metabolism to use the increased lactate and made them resistant to radiation and chemotherapy.
“Tumours are able to change the pathways they're using to switch from glucose to lactate, as a resistance mechanism,” says Colbert. “However, we do not fully understand exactly how this metabolic rewiring occurs. This is an area that researchers are very interested in right now.”
Implications in cervical cancer and beyond
The team is now investigating whether the lactate-producing bacteria could be eliminated from the vaginal microbiome using targeted antibiotics that don’t interfere with healthy vaginal microbes. Another avenue for research could be to engineer L. iners to work as a ‘Trojan horse’ to target tumours. Casting the net wider to other bacteria and cancers, researchers could look to investigate why using lactate for fuel appears to be more common in squamous cancers.
The study’s findings could have a profound influence on the treatment of cervical cancer, but the impact could be felt in oncology more widely. The team at MD Anderson observed a strong connection between other tumour-associated lactate-producing bacteria and poor clinical outcomes across other cancers — 40% of genetically similar species were associated with a reduction in RFS in lung, colorectal, skin, and head and neck cancers. These bacteria could be promising therapeutic targets across many types of cancer.
“We’re hopeful that our initial research will lead us to approaches that can benefit patients across several types of cancer. There's a lot of preclinical work to do, but I can see the translation to patients,” says Colbert. “That’s exciting.”