Image: High-resolution microscopy of a mesenchymal cancer cell that has been killed by inactivating the CDS2 gene. Prior to cell death, tiny lipid droplets accumulated, which are still visible as cyan-colored dots, visualized using fluorescence microscopy. The DNA of the dead cancer cells (magenta) is dispersed throughout the surrounding area.
Processed image by Tim Arnoldus, Gemma Driessen and Marjolein Mertz. Legend: magenta = DNA from dead cancer, cyan = lipid droplets
Researchers usually conduct laboratory experiments to identify the genes that cancer cells rely on for their growth and survival, with the premise that inhibiting such genes could stop or kill cancer cells. However, PhD student Tim Arnoldus took a different approach. He used large databases containing information on gene activity in all types of cancer as well as healthy tissues. Using advanced computational analyses, he screened for new vulnerabilities in cancer. These large-scale analyses led him to a weak spot that could serve as a target for novel treatments. The researchers used a principle called “synthetic lethality”, in which inhibiting either of two genes individually does not kill the cancer cell, but inhibiting both simultaneously does. A precedent for clinical application of this mechanism is olaparib, a medicine for hereditary breast and ovarian cancer, cancer types in which the PARP protein has become essential due to a mutation the BRCA gene.
Arnoldus identified another synthetic lethal relationship between CDS1 and CDS2, two highly similar genes. Every cell in our body needs at least one of these genes to survive. He discovered that the CDS1 gene is inactive in mesenchymal-like cancers, making them fully dependent on CDS2 for survival. Arnoldus demonstrated in cell cultures and mouse models that inhibiting the CDS2 gene does indeed leads to the death of cancer cells. Both CDS1 and CDS2 are active in healthy tissue, so inhibiting only CDS2 does not cause cell death.
Mesenchymal-like cancers arise from epithelial cells that have undergone a process known as epithelial-to-mesenchymal transition (EMT). Roughly half of all cancers exhibit these characteristics; they frequently metastasize and respond poorly to treatment.
Arnoldus then investigated the mechanism and found that inhibiting CDS2 causes cancer cells to accumulate tiny lipid droplets. This aligns with CDS2’s role in building structural lipids from these droplets, which are essential for cell survival. When this process is disrupted by CDS2 inactivation, the building blocks accumulate, causing a shortage of essential lipid molecules leading to cancer cell death. Encouragingly, computational analyses and experiments suggest that it won’t be easy for cancer cells to develop resistance to CDS2 inhibition.
While no CDS2-selective inhibitors currently exist, Arnoldus and Peeper have initiated collaborations with medicinal chemistry groups to develop these compounds. Achieving sufficient selectivity over the closely related CDS1 may prove challenging, but early in silico and structural data suggest that this may be feasible.
This research was funded by Oncode Institute and KWF Dutch Cancer Society.