Glen Clack, Lecturer in Faculty of Health and Life Sciences Departmen at University of Exeter Medical School, shared a post on LinkedIn:
”There is a comfortable orthodoxy in oncology which holds that the way to see off a tumor is to damage its DNA thoroughly enough; inflict sufficient injury, the reasoning runs, and cell death follows as night follows day. A splendid new preprint from Nick Li, Chris Tape and colleagues at UCL and Glasgow sets the cat among the pigeons on precisely this point.
Working in rectal cancer, where some 85% of patients fail to achieve a complete response to neoadjuvant chemoradiotherapy, the authors interrogated 2,769 patient-derived organoid cultures at single-cell resolution.
The central finding is as elegant as it is discomfiting: proliferative and ‘revival’ stem cells drawn from the very same tumor sustain identical DNA damage after irradiation, yet only the proliferative ones die. The revival cells resolve the damage, shrug, and persist as drug-tolerant survivors; and chemoradiotherapy itself, aided and abetted by the surrounding fibroblasts, actively herds cells into this resistant state.
The therapeutic moral is not to hit harder but to govern the fate into which the damage lands. Constraining that plasticity, notably via YAP/TEAD inhibition, converts a tolerated insult into a lethal one.
For those of us laboring in the DNA-damage-response vineyard, the inference is a faintly minatory one: dose may be necessary, but it is emphatically not sufficient; the cell’s interpretive apparatus keeps the casting vote. Whether the window over normal gut proves generous or Procrustean is the question the clinic must now kick the tyres on.
Worth reading in full; hats off to the authors.”
Title: Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer
Authors: Nick Li, Fiza Ishaqwala, Thomas A. Wright, Alistair Wilkinson, Petra Vlckova, Katherine Trevers, Rhianna O’Sullivan, Shauna Crampsie, Ewa Basiarz, Sierra Vanderkamp, Ashley K McCulloch, Aurelie Dobric, Smita Krishnaswamy, Bart Vanhaesebroeck, Glasgow Serial Sampling Consortium, Campbell S. D. Roxburgh, Maria Hawkins, Christopher J. Tape.
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