Highlighted Paper: CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction

The Translational Cancer Therapeutics Lab headed by Charles Swanton has pulished this paper in the Journal of Pathology this month.

Lee AJ, Roylance R, Sander J, Gorman P, Endesfelder D, Kschischo M, Jones NP, East P, Nicke B, Spassieva S, Obeid LM, Juul Birkbak N, Szallasi Z, McKnight NC, Rowan AJ, Speirs V, Hanby AM, Downward J, Tooze SA, Swanton C. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. J Pathol. (Abstract)

 

Our group  identified a protein  called CERT (CERamide Transporter), in a large scale experiment to identify regulators of chemotherapy drug sensitivity in breast, colon and lung cancer cells. We have been studying the function of this protein and how it enables cells to survive the onslaught of chemotherapy treatment. We have found that eliminating this protein from cancer cells induces sensitivity to chemotherapy induced cell death by engaging a pathway called Autophagy which can destroy the cell from the inside. Through tracking of live cancer cells, we have found that eliminating CERT induces the death of cells with too many chromosomes, following treatment with the breast cancer drug paclitaxel.

This prompted our group to examine whether expression of CERT might be linked to chemotherapy sensitivity and resistance in breast cancer. We found that low expression of CERT correlated with relatively improved outcome following breast cancer chemotherapy indicating that defining the amount of this protein in cancer cells prior to chemotherapy may help to determine which patients derive more benefit from treatment. We are attempting to confirm these findings in a larger cohort of breast cancer patients treated within the TACT adjuvant chemotherapy clinical trial.

Co-localisation of LAMP2 and LC3 upon CERT silencing and paclitaxel treatment. LAMP2 expression is required for death of polyploid cells following CERT depletion.