A new paper in the Proceedings of the National Academy of Sciences (PNAS) by Dr. Johanna Michl and Professor Pawel Swietach at DPAG has identified CEACAM6 as a marker for acid-resistance in colorectal cancer cell lines. This discovery could allow improved drug targeting to the tumour microenvironment, which is typically acidic.
Similar to hypoxia, extracellular acidity is a common feature of many solid tumours. It is caused by the higher metabolic rate of cancer cells and their lack of healthy blood vessels. How cancer cells survive in this hostile environment is incompletely understood.
The study by Michl et al. shows that colorectal cancer cell lines which are resistant to high levels of acidity express higher levels of the cell adhesion protein CEACAM6, and its related isoform CEACAM5. Both proteins are expressed on the surface of cancer cells. Therefore, they offer a means for targeting therapies to acid-resistant regions within the tumour.
The team also shows that CEACAM6 levels are induced under acidic conditions in several colorectal cancer cell lines. Surprisingly, inactivation of CEACAM6 (but not CEACAM5) reduced cell cancer growth. The team has previously shown that therapeutically targeting the mitochondrial OXPHOS pathway in combination with acid stress could be a promising cancer treatment option (Michl et al., 2022, Cell Reports). However, many OXPHOS inhibitors tested as cancer therapies have shown unacceptable side effects. Using antibody-drug conjugates with OXPHOS inhibitors, such as atovaquone as cargo and specifically targeting them to acidic regions marked by CEACAM6 may provide a promising strategy. This approach would reduce concerns about off-target reactions of OXPHOS inhibitors, and lessen potential side effects. Given CEACAM6’s important role in promoting cell growth, blocking its function using siRNAs or inhibitory antibodies without any additional cargo also deserves further research.
Dr. Johanna Michl said “We are excited to have discovered a critical marker for acid-resistance, which may be used to deliver drugs to tumour tissues more effectively, and therefore reduce side effects in patients. We believe that CEACAM6 plays a role in colorectal cancers and several other tumour types.”
Image: CEACAM6 is expressed in late-stage human colorectal tumour tissues. Representative images of CEACAM5 (red), CEACAM6 (green), and DAPI (blue) fluorescence in matched pairs of human normal colon and tumour formalin-fixed paraffin-embedded (FFPE) tissue sections from colorectal cancer patients.
Read the paper here