The team of prof. Sarah-Maria Fendt (VIB-KU Leuven Center for Cancer Biology) has found that the processing of a particular nutrient in the lungs boost the signals that promote the growth of metastatic tumors. This discovery may allow us to predict the response of breast cancer patients with lung metastases to the drug Sirolimus. The study – supported by Kom Op Tegen Kanker, FWO, and ERC – appears in Molecular Cell.
Different activation of growth signals
Metastatic breast cancers, which are breast cancers that have spread to different organs, unfortunately do not yet have a cure. Current treatment strategies for metastatic breast cancer focus on therapies that have been developed for primary breast cancer rather than considering the organ in which the metastasis grows.
The team of prof. Fendt now discovered that primary breast cancers and the resulting lung metastases differently activate the signals cancer cells use to sustain tumor growth. They found that the nutrient pyruvate, which is available in the lung, activates a particular metabolic pathway (the serine biosynthesis pathway) in the metastases. The consequence of this activation is an increase in the signals that cancers require to grow. Strikingly, in the primary breast tumors, pyruvate and the serine pathway were not necessary to activate these growth signals.
Dr. Rinaldi, the lead author of the study, says: “Our findings highlight that primary and secondary tumors rely on distinct mechanisms to support their growth. This explains why they respond differently to therapies. In particular, our preclinical models reveal the activation of a specific metabolic pathway by pyruvate that is crucial to potentiate growth signals via a protein known as mTORC1."
Sirolimus is a drug that inhibits the growth signals relayed through the protein mTORC1, and it is being tested in clinical trials for metastatic breast cancer after already being approved for other conditions. The work of prof. Fendt’s research team could be used to predict the response of patients with breast cancer-derived lung metastases to Sirolimus. Moreover, new therapeutic strategies may arise from this study.
Prof. Fendt explains: “Based on the current study from Dr. Rinaldi and our previous studies from Dr. Elia and Dr. Christen, developing drugs that inhibit the ability of cancer cells to take up pyruvate could allow us to prevent and treat metastatic lung tumors in breast cancer patients.”
Rinaldi et al. (2020). In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis but not of primary breast tumors to mTORC1 inhibition. Molecular Cell.
GR (first author from the Fendt Lab) received consecutive Ph.D. fellowships from Kom op Tegen Kanker and FWO (1137117N and 1137119N). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator Grant Agreement n. 771486–MetaRegulation, FWO – Research Projects (G088318N), KU Leuven – Methusalem Co-Funding and Fonds Baillet Latour.
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