Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases

Reviewer #1 (Public Review):

Summary:

In this manuscript, the authors suggest that Keratin 17 (K17) a component of intermediate filaments that is highly expressed in the more aggressive basal subtype of pancreatic cancer, is functionally involved in tumor promotion. They use mouse and human cell lines and overexposed wild type or mutant K17 (the latter a form that accumulates in the nuclei) and show a modest reduction in survival and increase in tumor size and metastasis. The authors use in vitro work to show that phosphorylation, through a PKC/MEK/RSK kinase cascade, leads to K17 phosphorylation and K17 disassembly.

Strengths:

K17 is an intriguing protein, as it becomes part of intermediate filaments but it has also been described to have a role in the nucleus. Whether K17 functionally drives the malignant phenotype of pancreatic cancer is unclear. Thus, the article addresses an important area of research.

Weaknesses:

Some shortcomings with the interpretation of results and the strength of the evidence provided are notes. Among those, evidence that nuclear K17 is a feature of basal pancreatic cancer in human tumors is missing. Further, the survival effects observed in the mouse experiments are modest, especially with the L3.6 cell line. Lastly, while the authors point at some potentially intriguing gene expression changes in pancreatic cancer cells expressing K17, such as the expression of genes related to epithelial mesenchymal transition (EMT) they do not provide evidence that these genes are K17 targets, not that they mediate the nuclear function of K17 in experimental models, nor that they are associated with K17-high human tumors.

Reviewer #2 (Public Review):

Summary:

Keratin 17 is a highly stress-inducible keratin that has been implicated in various human disorders. For example, higher K17 expression was shown to be associated with poor survival in several cancers including pancreatic carcinoma. To follow up on these observations, Kawalerski et al. assessed the relevance of K17 and its phosphorylation on this deadly tumor. In particular, they identified novel K17 phosphorylation sites and demonstrated that they affect K17 solubility as well as its nuclear localization. They also studied their significance in vivo.

Strengths:

The overall structure is very logical, the manuscript is well-written.

Weaknesses:

Unfortunately, the key experiment, i.e. the assessment of growth of cancer cell lines with different phospho-variants of K17, turned largely negative.