Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a provisional response from the authors.
Read more about eLife’s peer review process.Editors
- Reviewing EditorSendurai ManiBrown University, Providence, Rhode Island, United States of America
- Senior EditorWafik El-DeiryBrown University, Providence, United States of America
Reviewer #1 (Public Review):
Summary:
This study presents a valuable finding on the increased activity of two well-studied signal transduction pathways - STAT-3 and TGF-Beta in a specific subtype of pancreatic cancer. Specifically, SMAD4 deficient tumors (commonly observed in pancreatic cancer) are well differentiated in the presence of STAT3. Yet surprisingly, in the presence of SMAD4 in a STAT-3 deficient pancreatic cancer, the phenotype is poorly differentiated in the background of KRASGD12D. The evidence in the animal models supporting the authors' claims is solid, although including TCGA data and/or a larger number of patients would have strengthened the study. The work will be of interest to medical biologists working on pancreatic cancer and potentially the broader field.
Strengths:
Strengths are the animal models and the lead author's expertise in STAT3 signaling.
Weaknesses:
Weaknesses are the absence of correlation between the results from the animal studies and human pancreatic cancers.
Reviewer #2 (Public Review):
Summary:
This manuscript explores mechanisms by which STAT3 may regulate KRAS mutant cancers.
In the first set of experiments, STAT3 GOF mutants diminished the transformation of p53-null mouse embryonic fibroblasts expressing endogenous mutant KRAS(G12D) (KP MEFs) and this was dependent on direct transcriptional activation induced by phosphorylated STAT3. It appears that this is mediated via a reduction in TGFb signaling such that knockout of either TGFBR2 or SMAD4 can phenocopy the effects of STAT3 GOF mutants in KP MEFs.
In the next part of the paper, the authors used murine pancreatic ductal adenocarcinoma (PDAC)-derived cell lines bearing endogenous KRAS(G12D) and TP53(R172H) mutations (KPC) to determine the extent to which STAT3 may regulate KRAS dependency. They determined that KRAS and STAT3 KO both induced mesenchymal-like phenotypes and that TGFBR2 and SMAD4 KO induced epithelial phenotypes. The loss of STAT3 appeared to correlate with a KRAS-independent signature, and SMAD4/TGFBR2 KO could not induce epithelial phenotypes when STAT 3 was also knocked out.
Strengths:
Overall, this is an interesting paper that highlights the complicated interactions between KRAS, STAT3, and TGF beta signaling. The authors use multiple models and attempt to link data to patient cohorts.
Weaknesses:
While correlations are strong, the study would benefit from additional cause-and-effect type experiments. It would also be beneficial to better tie together the first and second parts of the paper.