Sensitisation of cancer cells to radiotherapy by serine and glycine starvation

Background: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. Methods: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. Results: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. Conclusion: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer

Early opening history of the North Atlantic - I. Structure and origin of the Faeroe-Shetland Escarpment.

Marine geophysical surveys show that the Escarpment is the buried feather-edge of a thick pile of flood basalts of early Eocene age, overlying a thinner, more widespread layer of basalts of late Palaeocene age. The Escarpment does not, therefore, define the continent—ocean boundary in the southern Norwegian Sea, but instead marks the contemporary shoreline separating terrestrially erupted basalt flows in the north from a restricted shallow-water shelf to the south. The basalts overlie 5–6 km of Mesozoic sediments, which have completely buried a large conical flat-topped seamount of similar dimensions to Anton Dohrn and Rosemary Bank. We call this newly postulated body the Brendan seamount. The Mesozoic sediments are at least as old as early Cretaceous in age, therefore precluding the possibility that the mid-Cretaceous seafloor spreading episode (supposed by some to have created the Rockall Trough) could have also created the thin crust inferred to underlie the Faeroe—Shetland Trough and Møre Basin