Cancer Biology

Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation

1. Gaurav Mendiratta
2. Edward Stites

• Curated by eLife

  eLife assessment

  This important study uses mathematical modelling to demonstrate that conformational autoinhibition of the RAF kinase is an important feature of its paradoxical activation by pharmacological inhibitors. This part of the theoretical analysis is highly compelling but its extension to the investigation of how the binding of 14-3-3 adaptors additionally contributes to the paradoxical activation phenomenon is incomplete and would benefit from more rigorous experimental validation. With the experimental part addressing 14-3-3-dependent regulation strengthened or the 14-3-3 part completely removed, this paper would be of considerable interest to cell biologists and cancer biologists, ultimately paving the way for improved RAF therapeutics.

Reviewed by eLife

ONC201/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer

1. Elena Farmaki
2. Aritro Nath
3. Rena Emond
4. Kimya L Karimi
5. Vince K Grolmusz
6. Patrick A Cosgrove
7. Andrea H Bild

• Curated by eLife

  eLife assessment

  This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.

Reviewed by eLife

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

1. Changyu Zhu
2. Yadira M Soto-Feliciano
3. John P Morris
4. Chun-Hao Huang
5. Richard P Koche
6. Yu-jui Ho
7. Ana Banito
8. Chun-Wei Chen
9. Aditya Shroff
10. Sha Tian
11. Geulah Livshits
12. Chi-Chao Chen
13. Myles Fennell
14. Scott A Armstrong
15. C David Allis
16. Darjus F Tschaharganeh
17. Scott W Lowe

• Curated by eLife

  Evaluation Summary:

  This manuscript shows that mutations in the gene encoding an enhancer chromatin-modifying enzyme MLL3 cooperate with Myc overexpression to drive hepatocellular carcinoma in mouse models. The authors identify Cyclin Dependent Kinase Inhibitor 2A (Cdkn2a) as a critical direct target gene of MLL3. Overall, the manuscript makes a compelling case that MLL3 is a hepatocellular carcinoma tumor suppressor that directly binds and activates the Cdkn2a locus. This study provides important insights for cancer biologists and those interested in specific epigenetic mechanisms that regulate liver cancer development. Editorial and some experimental suggestions were made to strengthen the work.

  (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. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Reviewed by eLife

eRNA profiling uncovers the enhancer landscape of oesophageal adenocarcinoma and reveals new deregulated pathways

1. Ibrahim Ahmed
2. Shen-Hsi Yang
3. Samuel Ogden
4. Wei Zhang
5. Yaoyong Li
6. The OCCAMs consortium
7. Andrew D Sharrocks

• Curated by eLife

  Evaluation Summary:

  In this manuscript, the authors identify enhancer-associated (e)RNAs that are specifically associated with esophageal adenocarcinoma. Based on combining the data with analyses of patient gene expression data and epigenetic data from cell lines, they conclude that eRNAs are markers of enhancers relevant to the transition from Barrett's esophagus to cancer. This work provides new insights into the epigenetic alterations that occur in cancer progression, and it will be of interest to the cancer and epigenetics fields.

  (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. Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis

1. Ricardo A Cordova
2. Jagannath Misra
3. Parth H Amin
4. Anglea J Klunk
5. Nur P Damayanti
6. Kenneth R Carlson
7. Andrew J Elmendorf
8. Hyeong-Geug Kim
9. Emily T Mirek
10. Bennet D Elzey
11. Marcus J Miller
12. X Charlie Dong
13. Liang Cheng
14. Tracy G Anthony
15. Roberto Pili
16. Ronald C Wek
17. Kirk A Staschke

• Curated by eLife

  Evaluation Summary:

  This manuscript is an important body of work that addresses the role of the integrated stress response (ISR) and the role of the GCN2 protein kinase in prostate cancer. The studies comprehensively elucidate how GCN2 and amino acid transporters and uptake promote prostate cancer proliferation, as well as the therapeutic potential of inhibiting this pathway. This work, therefore, provides insights for both identification of new mechanisms and experimental therapeutics in prostate cancer.

  (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. Reviewer #2 agreed to share their name with the authors.)

Reviewed by eLife

Nuclear fascin regulates cancer cell survival

1. Campbell D Lawson
2. Samantha Peel
3. Asier Jayo
4. Adam Corrigan
5. Preeti Iyer
6. Mabel Baxter Dalrymple
7. Richard J Marsh
8. Susan Cox
9. Isabel Van Audenhove
10. Jan Gettemans
11. Maddy Parsons

• Curated by eLife

  Evaluation Summary:

  This work explores a topic of high interest to cell and cancer biologists - the role of actin polymerization, and here specifically the role of fascin, in the nucleus. The authors show that fascin regulates nuclear actin, chromatin organization, response to DNA damage, and demonstrate the need for control of steady-state nuclear levels to avoid cell death. Studying nuclear actin is technically challenging, and the authors deploy some novel technologies towards this goal. There are some very elegant experiments in this paper that suggest fascin has an important role in regulating nuclear actin and other important aspects of cancer cell behaviour. The work could be enhanced by the authors considering adding some additional experiments and providing clarifications and some further details or discussion.

  (This preprint has been reviewed by eLife. We include the joint public review from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All three Reviewers agreed to share their names with the authors.)

Reviewed by eLife

The “LINC” between Δ40p53-miRNA Axis in the Regulation of Cellular Homeostasis

1. Apala Pal
2. Pritam Kumar Ghosh
3. Saumitra Das

Reviewed by Review Commons

Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation

1. Hae J Park
2. Mark A Gregory
3. Vadym Zaberezhnyy
4. Andrew Goodspeed
5. Craig T Jordan
6. Jeffrey S Kieft
7. James DeGregori

• Curated by eLife

  Evaluation Summary:

  FLT3 (Fms Related Receptor Tyrosine Kinase 3) activation occurs in a subset of acute myeloid leukemia (AML) cases and is associated with poor prognosis. This work is focused on the mechanisms of resistance to FLT3 inhibitors in AML. The authors show that the combination of the FLT3 inhibitor and an mTORC1 inhibitor reduces tumor burden and prevents relapse in FLT3 mutant AML. This paper is of interest in scientists and physicians investigating AML as well as scientists studying signaling pathways.

  (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.)

Reviewed by eLife

Cancer stem cell-derived extracellular vesicles preferentially target MHC-II–macrophages and PD1+ T cells in the tumor microenvironment

1. Patricia Gonzalez-Callejo
2. Zihan Guo
3. Tahereh Ziglari
4. Natalie Marcia Claudio
5. Kayla Hoang Nguyen
6. Naoki Oshimori
7. Joaquim Seras-Franzoso
8. Ferdinando Pucci

Reviewed by Review Commons

The scaffolding protein flot2 promotes cytoneme-based transport of wnt3 in gastric cancer

1. Daniel Routledge
2. Sally Rogers
3. Yosuke Ono
4. Lucy Brunt
5. Valerie Meniel
6. Giusy Tornillo
7. Hassan Ashktorab
8. Toby J Phesse
9. Steffen Scholpp

• Curated by eLife

  Evaluation Summary:

  The manuscript by Routledge et al. describes the role of Reggie-1/Flottilin2 in the formation of filopodia-like membrane protrusions called cytonemes and which were shown to be conserved between gastric cancer cells and Zebrafish. Authors demonstrate that Flot2 is present on the cytoneme along with Wnt3 in gastric cancer and with Wnt8a in Zebrafish. Furthermore, Flot2 is also present with Ror2 on the cytoneme and together they are believed to modulate cytoneme formation. This study extended the previous studies and provides new details about regulatory events controlling a cell biological process that will be of interest to those in the Wnt and cytoneme fields.

  (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.)

Reviewed by eLife