5th de Duve Lecture: Watch the podcast!
Pascale Cossart enlightens us on the molecular and cellular bases of bacterial infections.
The Lambertine Lacroix Prize is awarded every two years by the FNRS to a Belgian researcher aged 50 years or less, alternately for research in cancer and for research on cardiovascular diseases. It rewards fundamental research, preferably with translational implications. It was awarded to Nick van Gastel on Thursday 5 May for his work on the elimination of residual leukemia cells after chemotherapy.
Chemotherapy remains the standard treatment for acute myeloid leukemia (AML), but in most patients a small number of cancer cells survive in the bone marrow and eventually cause relapse. Developing new therapies to eliminate these residual cells is therefore of great clinical importance.
It remains unclear how certain AML cells manage to survive the extreme stress of chemotherapy. Most research related to relapse has focused on specific mutations that would confer chemoresistance in a subset of cells, but thus far this has not led to new therapies. In our research, we are taking a different approach to the problem of chemoresistance. Rather than genetics, we focus on cellular metabolism. Cellular metabolism is the large, highly integrated network of biochemical reactions that provides cells with metabolic energy, reducing power and biosynthetic intermediates. Metabolic networks also endow cells with rapid stress-protection systems that are independent of transcriptional changes, providing a first-line defense mechanism to cope with exogenous pressure.
To investigate whether chemotherapeutic stress imposes a metabolic bottleneck where only a few highly-adaptable AML cells survive, we developed a set of novel metabolic analysis tools allowing us to study the metabolism of AML cells in the bone marrow of mice. We discovered that residual AML cells have a unique metabolic profile, distinct from the pre-chemo or post-chemo relapse phases. More detailed analyses revealed that persisting cells take up large amounts of the amino acid glutamine to fuel the synthesis of nucleotides, the building blocks of DNA and RNA. Blunting glutamine metabolism or nucleotide synthesis selects against residual leukemia cells and improves survival in leukemia mouse models and patient-derived xenografts. Timing is crucial however, as giving the metabolic inhibitors too early or too late does not have the same efficacy as hitting the moment of maximal vulnerability immediately following chemotherapy.
In conclusion, our work introduces the concept that metabolic adaptability, and not only genetic predisposition, drives chemoresistance. Our work forms the basis for future clinical studies testing the timed use of nucleotide synthesis inhibitors in AML patients undergoing chemotherapy. It also justifies investigating the concept of a unique metabolic bottleneck associated with chemotherapy in the treatment of other tumor types.
Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance.
van Gastel N, Spinelli JB, Sharda A, Schajnovitz A, Baryawno N, Rhee C, Oki T, Grace E, Soled HJ, Milosevic J, Sykes DB, Hsu PP, Vander Heiden MG, Vidoudez C, Trauger SA, Haigis MC, Scadden DT. Cell Metab. 2020 Sep 1;32(3):391-403.
Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
van Gastel N, Spinelli JB, Haigis MC, Scadden DT. Bio Protoc. 2021 Oct 5;11(19):e4171.