Pierre SONVEAUX
Head, TUMETABO team
Université catholique de Louvain
Brussels
BELGIUM
Website Pierre Sonveaux
Programm
”Identification and targeting of metabolic sensors controlling (tissue-specific) cancer metastasis”
The metastatic switch is a discrete event that marks the transition from a localized to a systemic cancer disease. Clinically, the occurrence of distant metastases also usually marks the transition between curative to palliative care.
During the metastatic switch, some cancer cells acquire key characteristics, including resistance to anoïkis, mesenchymal and stem cell traits, migration and invasion capabilities and resistance to redox stress, all contributing to the metastatic progenitor cell phenotype. Selection occurs in metabolically hostile areas within the primary tumor, which are characterized, e.g., by hypoxia, restricted access to nutrients and acidosis. Only those cancer cells that have acquired all pro-metastatic characteristics together have the potentiality to generate a metastasis. They represent a tiny minority of circulating cancer cells.
In this context, we hypothesized, tested and validated in preclinical models of human cancers that metastasis can be prevented. Our working hypothesis was (1) that cancer cells in primary tumors should be equipped with metabolic sensor(s) informing about microenvironmental metabolic conditions, and (2) that each metastatic progenitor cell should be equipped with a second type of metabolic sensor informing about the type of nutrient(s) available in surrounding organs. According to the seed and soil hypothesis and in line with the premetastatic niche theory, the second type of sensor would control organotropism.
Using several types of human cancer cells nevertheless focusing on those frequently detected at the premetastatic stage in clinical practice, we report that cancer cell mitochondria are a key metabolic sensor controlling cancer cell dissemination from primary tumors. Through redox signaling initiated by superoxide production at the electron transport chain, mitochondria confer all the necessary traits to convert cancer cells to metastatic progenitor cells. This phenomenon can be prevented by using MitoQ, a mitochondria-targeted antioxidant that acts as a chain breaker in superoxide signaling. At clinically relevant nanomolar doses, full metastasis suppression was obtained in some models (triple negative human breast cancer for example), and partial inhibition in others (such as human pancreatic cancer). Concerning organotropism, we report that Cox7b, a structural component of electron transport chain Complex IV, is responsible for brain metastasis in a model of human breast cancer: silencing COX7B prevented brain metastasis, whereas overexpressing COX7B experimentally selectively triggered the homing of metastatic progenitor cells in the brain. Cox7b might not be unique for brain tropism, and other sensors would control the colonization of other organs.
Overall, this piece of work demonstrates in mice that cancer dissemination can be retarded and even prevented in some cases, which, if translated in clinical settings, would increase the chances of cure of cancer patients. A major incentive to move forward is that MitoQ already passed safety Phase I clinical trials.
Host: Martin HOHENEGGER
Contact for questions: Helmut KUBISTA