Scientists identify multiple cell types that may contribute to treatment resistance in prostatecancer elife elife
for the benefit of readers; feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Thank you for submitting your article"Defining cellular population dynamics at single cell resolution during prostate cancer progression" for consideration by.
Pg 7, lines 290-304. AR activity in intermediate cells was compared between WT, intact and castrated PTEN-null samples. Line 300, differentiated cells retain high AR activity in intact PTEN-null but because population is absent in castrate mice , how is final conclusion about"luminal cells", broadly, arrived at?
Figure 1: The proposition that basal cells are differentiating into intermediate luminal cells is intriguing, but could just as easily be an artifact of trajectory analysis or the activation of Pten in basal epithelia . It also defies the current paradigm that prostate luminal epithelia undergo lineage plasticity in castration and when mutated. Therefore, I would suggest hedging this bet in the conclusion.
The observation that the castrate Pten intermediate epithelial signature is enriched in aggressive disease is not too surprising as this may just reflect castration. What would be interesting is to know how this model compares to other models of castration resistance like Rb/p53 null mice.Line 488: While it's true that the transdifferentiation, an intermediate luminal phenotype is absent in the wild-type mouse, this phenotype does appear in castrate WT mice.
2) There should be some additional emphasis placed on the human level validation for the central findings in this work. We agree with the reviewer that additional discussion of follow-up studies is necessary. As such, we have updated the discussion to highlight the molecular studies needed to fully characterize the cellular phenotypes described in this manuscript .We outline epithelial-macrophage signaling interactions in lines 310-315 , showing both the presence of ligand-receptor interactions and the increased expression of epithelial ligands in Ptenfl/fl mice.
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