A team of researchers led by Dr. Guangwen “Gary” Ren and Dr. Leonard “Lenny” Shultz from The Jackson Laboratory in Bar Harbor, Maine, has discovered that lipid-laden neutrophils, induced to acquire lipids by mesenchymal cells, foster the survival and growth of breast cancer metastases within the lungs.
Their work, published in the journal Nature Immunology, has provided insight into the mechanisms by which neutrophils accumulate lipids and transfer these energy-rich molecules to cancer cells, and suggests that inhibiting this process pharmacologically could attenuate metastatic cancer development.
“Our group worked on solid tumor metastasis, which is the major cause of death of cancer patients. Currently, there are no effective cures for metastatic disease. Among the multiple steps of metastatic progression of solid tumors, tumor cell colonization in distant organs is one of most critical and rate-limiting steps,” Dr. Guangwen Ren explained to ImmunoFrontiers.
“Our research focus is to dissect the mechanisms underlying how organ (lung, in this study) environmental cells coordinate the disseminated tumor cells for their successful colonization.”
“Previous studies regarding the organ stroma-tumor cell interactions mainly focused on the transcriptional and protein levels but characterized the metabolic level to a lesser degree. The motivation of our work was to determine whether a metabolic crosstalk exists between the organ stroma and metastatic tumor cells.”
“Our hypothesis was that lung immune microenvironment serves to metabolically support the successful colonization of metastatic tumor cells, which we approached using RNA-seq, flow cytometry, real-time PCR, fluorescent microscopy and in vivo mouse models of breast cancer.”
“The most important point of our study is that immune cells are able to serve as the energy source to support metastatic tumor cell survival and growth in an organ environment. This is critical for the disseminated tumor cells when they start to adapt into a new tissue environment and are in urgent need of nutrients.”
The team’s research findings could contribute to the discovery of novel targets for the prevention and treatment of metastatic cancer. “Our findings may open a field to study the metabolic interaction between the tissue immune microenvironment and disseminated tumor cells in solid tumor metastasis. To study such interactions would help define new targets in prevention and treatment of metastatic disease,” stated Dr. Ren.
“Secondly, our work showed that neutrophils are tissue-specific in gene expression and their regulatory effects on tumor cells. The tissue resident stromal cells play a key role in endowing the tissue-specific features of neutrophils. This may stimulate the future work on tissue-specific neutrophils and the tissue stroma-immune cell interactions in steady and pathological states.”
Moving forwards, the scientists plan to characterize molecular mechanisms involved in breast cancer metastasis at other organs in addition to the lungs.
“We plan to do comprehensive metabolomics analyses of the vital organs prone to metastasis in breast cancer models. From a basic science viewpoint, that will facilitate our deeper understanding of the metabolic interaction between the disseminated tumor cells and the tissue environment. From a translational perspective, that will help develop precise and novel treatments targeting the metabolic pathways in treating metastasis.”
Dr. Ren’s take-home message for readers: “In cancer models, our work revealed that inflammatory cells known as neutrophils play an “adipocyte” role in lung metastasis of breast cancer. The take-home message is whether this lipid-laden neutrophil phenotype also exists in other pathological contexts such as infectious diseases, and if so, which functions are served by lipid-laden neutrophils in other pathological conditions.”
Li P, Lu M, Shi J, et al. (2020) Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat Immunol, 21(11): 1444-1455.