Tumor cells reprogram the brain to promote metastasis

Researchers from the National Cancer Research Center (CNIO) have revealed how some of the molecular changes that reprogram the brain to develop metastasiswhich opens new avenues for its treatment.

In almost a third of cancer patients the tumor reaches the brain and metastasizes. This process has traditionally been considered the final stage and without options of a aggressive cancerto the point that those who reached it were excluded from clinical trials due to their poor prognosis.

The CNIO team, led by Manuel Valiente, has expanded the focus of the research to what is happening in the environment of brain metastasis. The results of this laboratory over the last decade allow us to conclude that metastasis develops when tumor cells create an environment to their liking, and to do so “they must alter the brain themselves,” explains Valiente.

When the tumor cells reach the brain, most are eliminated, since they hardly have the tools to grow in this organ.; Only a few have the necessary skills to reshape the brain and adapt it to their liking. Tumor cells begin to change the tissueto activate molecular pathways that should be turned off and, ultimately, to create an environment that only they find welcoming. This allows them to proliferate uncontrollably and reproduce the tumor.

Now they have discovered another mechanism that could have value in brain metastasis from various types of tumors, and also in other pathologies that affect the brain without being tumorous. The discovery, which is published this Wednesday in the magazine Cancer Researchwith Laura Álvaro-Espinosa as first author, points out that in addition to this mechanism that There is a drug that penetrates well into the brain and is well tolerated.as it is approved as an asthma treatment in other countries. Valiente aspires to start a clinical trial in the medium term.

Ibudilast works by blocking the binding of MIF to CD74

The new target is a protein called MIFwhich, produced by tumor cells in the brain, it would act as a key that is never used in this organ. The new study shows that MIF binds to a molecular structure – called CD74 – found on the surface of a type of cell responsible for signaling the immune system, macrophages and microglia.

Under normal conditions these cells with CD74 would fight metastasisbeing part of the immune system; but with the molecular key MIFmetastatic cells use CD74 to make them work for the cancer. MIF reprograms this cell type to drive tumor growth.

Looking for how prevent MIF from transforming CD74 macrophages, the CNIO group found the drug ibudilastwhich is known to act by blocking the binding of MIF to CD74. Their results show that ibudilast slows brain metastasis, both in animal models and in fresh patient samples derived from different primary tumors. “We demonstrate that microglia and CD74+ macrophages are reprogrammed, and go from having a potentially anti-tumor to a pro-metastatic nature in the brain,” the researchers write in Cancer Research.