Fibroblast Growth Factor Receptor Functions in Glioblastoma

Round 1

Reviewer 1 Report

The manuscript „FGF receptor functions in glioblastoma” by Ana Jimenez-Pascual and Florian A Siebzehnrubl summarizes the current state of knowledge about the involvement of FGFRs in glioblastoma. The manuscript is concise, well written and contains all relevant information. However, I have few comments that in my opinion can further improve this manuscript.

1. The first part of the manuscript describing FGFR-dependent signaling would benefit from additional subchapter referring to how FGFRs can be modulated in the brain by other cell surface receptors and proteins, like G-protein coupled receptors GPCRs and cell adhesion molecules CAMs. The potential relevance of the receptor cross-communication for glioblastoma should be discussed.

2. Authors should include subchapter describing how, on the molecular level, imbalanced FGFRs can participate in oncogenesis (e.g. activating point mutations, overexpression, gene fusions etc..). This chapter will facilitate understanding of the next sections describing FGFRs in glioblastoma.

3. Authors should cite original papers, whenever possible. For example when describing the role of D1 domain in FGFRs autoinhibition authors miss several important experimental papers. The same is true for other chapters. Thus, I would recommend revising citations in the manuscript.   

4. Figures should be inserted in the manuscript in place where they are described and not at the end.

5. Line 61: such as

Author Response

Response to Reviewer 1: 

We thank this reviewer for their helpful comments. The specific points raised by this reviewer have been addressed and are responded to below:

Point 1: We have now added a new section 4, where we discuss crosstalk between FGFRs and other cell surface molecules, including GPCRs and CAMs. There are only a limited number of studies that describe crosstalk in GBM. To avoid being overly speculative in our review, we have kept this section brief, but we have discussed key studies where appropriate. 

Point 2: We have expanded the paragraph in the introduction that discusses genomic alterations of FGFRs to improve clarity. As the focus of our review is on FGFR functions in GBM, we find that a subchapter on FGFR genomic alterations in other cancers is beyond the scope, particularly as these changes are exceedingly rare in GBM. Nevertheless, we have included a new table summarizing major genetic changes and their relevance for oncogenesis and point the reader to key reviews summarising the oncogenic functions of FGFR imbalances.

Point 3: We have revised the cited references to include more original studies.

Point 4: The figures have been inserted into the text.

Point 5: This has been amended.

Reviewer 2 Report

This manuscript of a review article submitted for publication in Cells is a concise and detailed discussion of the role of FGFRs in glioblastoma (GBM).  Their hypothesis that “FGFR signaling needs to be maintained for the survival of GBM cells, and therefore evolutionary pressure selects against both activating and inactivating mutations” is very interesting.  There is a good discussion of FGFR subtypes, alternative splicing, FGF ligand binding, signaling cascades, receptor internalization, and current therapeutic strategies.  They point out where more work needs to be done at appropriate places in the review.  This review is a welcome and necessary addition to the literature.  It is well written. 

Their review of the current literature is fairly complete, but some important findings, which would make their review complete and more interesting, are absent.  For example, it has been known since the 1990s from the work of Frank Walsh and Patrick Doherty in London that NCAM, N-cadherin, and L1CAM signal through the FGFR by a unique mechanism to promote axon outgrowth in brain neurons during development.  GBM cells have been shown to express all three of these adhesion molecules, and this CAM-FGFR connection to GBM has been made in at least several papers in the literature (e.g., Mohanan et al., 2013 and Anderson and Galileo, 2016).  This adds A whole other layer of complexity to the function of FGFRs in GBM and ties them together with several different adhesion molecule and signaling systems.  The review only discusses FGF ligands as operating in GBM, which incorrectly makes the reader think that FGFs are the only possible FGFR ligands of interest to GBM.  A short discussion of CAM ligands and their implications for GBM should be in this review.

Glioblastoma is referred to as “cancers.”  Although GBM is very heterogeneous, it is still considered as one type of cancer, so it seems awkward to refer to it in the plural. 

Minor points:

Line 28: TACC should be defined for the reader.

Line 32: The sentence beginning with “Not only are…” is not a sentence.

Line 33: “passenger mutations” should be defined for the reader.

Author Response

Response to Reviewer 2: 

We thank this reviewer for their comments – indeed we agree that additional discussion of crosstalk between cell-adhesion molecules and FGFRs adds another dimension to our review. This has now been included in the new subsection 4. We have also included the references highlighted by this reviewer.

Minor points: 

(1) ‘TACC’ has been defined in the text.

(2) This has been amended. 

(3) ‘Passenger mutations’ are now defined in the text.

Reviewer 3 Report

In the manuscript entitled “FGF Receptor Functions in Glioblastoma” the authors reported a brief review on FGF receptor function in Glioblastoma. Despite the FGF receptor mutation are rare in these cancers, different studies have demonstrated that FGF pathway impacts glioblastoma progression and patient survival. The authors reported the evidence for the biological functions of FGF receptors in glioblastoma, as well as pharmacological approaches to targeting these receptors. They start from the description of the FGF pathway, then move to the description of each FGF receptor and the evidence for their role in glioblastoma; finally, the authors reported the possible therapeutic strategy involved the FGF receptor.

The manuscript is well written, and the topic is interesting. The manuscript is suitable for publication.

Author Response

Response to Reviewer 3: 

We thank this reviewer for their supportive comments.