Lipid metabolism controls lung cancer metastasis, not just diseases like atherosclerosis | 2020-09-30

Most cancer deaths ultimately occur as a result of metastasis. Previous reports have demonstrated that…

Lipid metabolism controls lung cancer metastasis, not just diseases like atherosclerosis | 2020-09-30

Most cancer deaths ultimately occur as a result of metastasis.

Previous reports have demonstrated that fat tissue can provide energy support to the disseminated tumor cells that increases the survival and proliferation of tumor cells in multiple solid tumor models leading to metastasis.

However, the metabolic communication between the metastatic tumor cells and the tissue environment are poorly understood.

Bone marrow-derived neutrophils in particular, are now known to be required for solid tumor metastasis.

While there are no significant fat tissues within the lung, a new study indicates that the inflammatory neutrophil cells play an “adipocyte-like” role in the lung metastasis of breast cancer.

Researchers working at the Jackson Laboratory Cancer Center reported in the September 21, 2020, issue of Nature Immunology that breast cancer cells induced neutrophils to accumulate lipids, which were transported to metastatic tumor cells through a macropinocytosis pathway, thus fueling the metastatic potential of tumor cells with lipids.

From a practical perspective, the work indicates that targeting the mechanisms of lipid storage in organ resident cells and the lipid macropinocytosis acquisition by tumor cells may be an effective approach in preventing and treating metastasis.

The research points to promising new pharmacotherapeutic targets involving inhibition of lipid storage or macropinocytosis for the prevention and treatment of solid tumor metastases.

Principal investigator, Guangwen Ren, assistant professor at the Jackson Laboratory, told BioWorld Science, “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.”

It was previously known that neutrophils nourish tumor cells via their secretome, which includes a variety of growth factors, cytokines, and extracellular matrix components. In this study it has now become clear that lung neutrophil-derived lipid stores are also being used by tumor cells to provide energy stores that ultimately increase the metastatic potential and deadliness of breast cancer cells.

Initial transcriptional screening of the genes upregulated in lung infiltrated myeloid cells (neutrophils) identified distinctive roles for lipid droplet-associated genes that were specific to lung neutrophils as compared to neutrophils in blood or bone marrow.

Next Ren’s group observed striking differences in lipids in lung neutrophils as compared blood or bone marrow neutrophils These included differences in morphology and lipid contents, but most significantly subsequent experimentation revealed that these lung lipid differences controlled the potential of tumor cell to metastasize.

Ren explained that lipid-laden myeloid cells such as macrophages, have been reported in the context of infectious diseases and that one exploited role of the lipids stored in macrophages has been to supply nutrients for invaded pathogens. By extension, “it is interesting to see that the metastatic tumor cells act as ‘pathogens,’ which fully take advantage of the host mechanisms for their spreading,” Ren said.

Interestingly, investigators also showed that tumor cells engulfed neutrophil-derived lipids, which led to an augmented proliferative capacity.

The long-term goal of Ren’s research program is to fully dissect the roles of organ-specific stromal cells in organ-tropic metastases of breast cancer. Inspired by mesenchymal cell-myeloid cell-tumor cell metabolic communications occurring in lung metastasis, he is particularly interested in studying the metabolic interactions between disseminated tumor cells and the organ environment during breast cancer metastasis to other organs such as bone, brain and liver.

Ren hypothesized that the mechanisms among different organs vary vastly, but that the key concept is similar – tumor cells will utilize the metabolites from the resident cells.

Next, Ren and his colleagues plan to perform comprehensive metabolomic analyses of vital organs prone to metastasis as well as giving attention to the possibility of roles whether glycolysis and other metabolic processes may also play roles in the lung stroma-tumor cell interaction. From the basic science aspect, this will facilitate a deeper understanding of the metabolic interaction between the disseminated tumor cells and the tissue environment. From a translational potential, this will help to develop precise and novel treatments for targeting the metabolic pathways in treating metastasis.

The Jackson Laboratory is currently developing and optimizing humanized mouse models (mouse with human immune system) and patient-derived xenograft (PDX) models. These research platforms will highly facilitate the translation of their basic science into clinical application.

Metastatic disease remains the major cause of cancer-related death, without any effective treatments. The ultimate goal of this research is to translate their basic research findings as quickly as possible into treatments to be used by patients with metastatic disease (Li, P. et al. Nat Immunol 2020, Advanced publication).

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