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  1. Reviewer #3 (Public Review):

    The paper has some novel insights implicating DR4 expression in oxaliplatin-resistant CRC as potentially a therapeutic vulnerability. The paper includes ex vivo treatment of oxaliplatin-resistant CRC CTCs with TRAIL liposomes and implication of DR4 localization of lipid rafts. The paper suggests that TRAIL pathway therapeutics may be helpful for oxaliplatin-resistance CRC. Such therapeutics have been tested in the past to treat CRC (TRAIL/Dulanermin in combination with FOLFIRI) but TRAIL development was discontinued due to lack of adequate patient responses. Currently TRAIL agonist antibodies are in various clinical trials including in combination with chemotherapy for CRC. While the findings are interesting, there are several major concerns with regard to data interpretation and experimental rigor. Based on limited data in the manuscript, the upregulation of DR4 does not appear to be a general mechanism associated with oxaliplatin resistance in CRC. The authors have not rigorously tested the role of DR4 in the sensitization to TRAIL. Similarly, the effect of resveratrol has not been rigorously attributed to DR4. Some data implicates DR5 in the sensitization (Supplementary Figure 6) but in the end the authors emphasize DR4. There could be other mechanisms involved.

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  2. Reviewer #2 (Public Review):

    Greenlee et al. describe a potentially new therapeutic approach for oxaliplatin-resistant (OxR) colorectal cancer (CRC). This group shows that OxR CRC cells have increased sensitivity to TRAIL-mediated apoptosis. Mechanistically, this work suggests enhanced DR4 palmitoylation and translocation into lipid rafts, and that perturbation of these LR impacts sensitivity of TRAIL. In support of this premise, treatment of blood samples with TRAIL liposomes caused a reduction circulating tumor cells (CTCs) from CRC patients. Collectively, these findings highlight a potentially translational avenue whereby CRC patients that acquire resistance to Oxaliplatin may benefit from treatments that target TRAIL-mediated cell death, including TRAIL-loaded liposomes. Overall, the work represents an interesting study with potential for translational relevance in CRC. However, some of the claims are not sufficiently rigorously backed by the data presented. For example, the claim that TRAIL-sensitized OxR cell lines have enhanced co-localization of DR4 to lipid rafts is supported by IF in Figure 4A, yet the Western blot data in Figure 4D is extremely modest and not reflective of this claim. Lastly, while there are data on lipid rafts in human CRC patients, the effects are on circulating tumor cells (CTCs), and there are no corroborating data on human metastatic lesions, or pre-clinical in vivo models of metastasis. In sum, while the findings are potentially interesting, more data would strengthen the claims and significance of the manuscript.

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  3. Reviewer #1 (Public Review):

    The novelty is that the sensitivity to TRAIL and co-localisation in lipid rafts is maintained in oxaliplatin-resistant cells post-treatment (previously shown in cells treated simultaneously with Oxaliplatin and TRAIL), and that this has the potential to target colorectal cancer cells through lipid-based TRAIL delivery. While the implications of the findings are compelling, the study would benefit from clarifying several open questions from the findings and demonstrating robust methodology.

    Specifically, the findings could be strengthened by improvements of the image and statistical analysis. The authors compare the area with stain positivity per cell, which assumes no morphological differences between OxR cells and parental cells and also relies on a threshold. To avoid this, robust methods would need to be used to compare the intensity distributions and pixel intensity spatial correlation. Furthermore, there is a lot of variability in the effect of reduced cell viability of circulating tumour cells across patients and draws. Inter- and intra-patient variation should be considered when statistically comparison the cell viability of circulating tumour cells to TRAIL-conjugated liposomes.

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  4. Evaluation Summary:

    The study investigates the molecular characteristics of chemotherapy-resistant colorectal cancer cells and proposes a therapeutic alternative for chemo-resistant cancer. The authors provide evidence in vitro that chemo-resistant cells are pro-apoptotic in the presence of the death receptor ligand TRAIL due to the enhanced localization of the death receptor DR4 in the lipid rafts of their plasma membrane. Based on this finding, the authors treat blood samples from 5 colorectal cancer patients with TRAIL-conjugated liposomes and observed reduction in the number of circulating cancer cells in the blood draws.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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