The article "Identification of functional and diverse circulating cancer associated fibroblasts in metastatic Castration Naïve” is an interesting scientific study that identify and characterize circulating CAFs. The article is developed in a standard way and the results are presented legibly. Overall, this article makes a valuable contribution to the field tumour microenvironment by evaluating the presence of cCAF that could help to prostatic cancer malignancy.
Minor comments
- It would be beneficial to include more details in the introduction about of heterogeneity of CAFs and functional diferences by subset identify in other studies of PCa
Major comments
To determinate functional differences in the subsets of cCAFs isolated the autors can performance the next experiments
- Its necessary a detailed characterization of isolated CAFs, using other techniques (e.g., collagen contraction and MMP secretion assays).
- Confirm by western blot CAFs-associated markers (FAP) and include other markers such as SMA, PDGFR and FSP1
- Perform functional assays such as proliferation, migration and invasion test using the CAFs isolated with PCa tumor cells lines.
- In the figure 6C,D. The morphology evaluated by IF is unclear. The autors could stain the cells with phalloidine to appreciate differences inthe morphology of cCAFs

Thanks to the author for answering my questions.
I understand the complexity and limitation of the study in terms of sample collection.
Therefore, subsequent studies, using methodology that allows categorizing/grouping the cCAFs present in this type of patients, would be important to carry out.