Cancer Biology

USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma

1. E. Josue Ruiz
2. Adan Pinto-Fernandez
3. Andrew P. Turnbull
4. Linxiang Lan
5. Thomas M. Charlton
6. Hannah Claire Scott
7. Andreas Damianou
8. George Vere
9. Eva M. Riising
10. Clive Da Costa
11. Wojciech W. Krajewski
12. David Guerin
13. Jeffrey Kearns
14. Stephanos Ioannidis
15. Marie Katz
16. Crystal McKinnon
17. Jonathan C. O’Connell
18. Natalia Moncaut
19. Ian Rosewell
20. Emma Nye
21. Neil Jones
22. Claire Heride
23. Malte Gersch
24. Min Wu
25. Christopher J. Dinsmore
26. Tim R. Hammonds
27. Sunkyu Kim
28. David Komander
29. Sylvie Urbé
30. Michael J. Clague
31. Benedikt M. Kessler
32. Axel Behrens

• Curated by eLife

  Summary:

  This paper is of general interest to cancer biologists focusing on identifying new targets for cancer therapy particularly in the context of squamous cell lung carcinoma. The authors demonstrate that genetic ablation of the deubiquitinase USP28 reduces the growth of lung squamous cell carcinomas but not lung adenocarcinomas in a mouse model of lung cancer, and that that this restriction of growth is accompanied by loss of expression of several USP28 targets. They also describe activity of a new small molecule compound in controlling the growth of lung squamous cell carcinomas in mouse genetic and xenograft models, and reducing expression of USP28 targets. They demonstrate that USP28 is one target of the newly identified compound, but they do not establish whether it is the only and biologically relevant target of this compound.

  Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Reviewed by eLife

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

1. Lisa Crozier
2. Reece Foy
3. Brandon L. Mouery
4. Robert H. Whitaker
5. Andrea Corno
6. Christos Spanos
7. Tony Ly
8. Jeanette Gowen Cook
9. Adrian T. Saurin

Reviewed by Review Commons

Signaling amplitude molds the Ras mutation tropism of urethane

1. Siqi Li
2. Christopher M. Counter

• Curated by eLife

  Evaluation Summary:

  This work helps explain some enduring mysteries about why certain activating mutations appear in the KRAS gene more frequently than others. This paper provides experimental support for an emerging concept within the Ras field that there is a sweet-spot of Ras signal strength that promotes tumorigenesis and that this explains why different mutations are observed in different contexts. The experiments are sound and the conclusions are fair. Given that certain KRAS mutations may be more amenable to therapeutic interventions than others, it is important to understand the basis for mutational tropism, and this work provides strong in vivo evidence that addresses this issue.

  (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 names with the authors.)

Reviewed by eLife

A systematic CRISPR screen reveals an IL-20/IL20RA-mediated peritoneal immune crosstalk to prevent the ovarian cancer metastasis

1. Jia Li
2. Xuan Qin
3. Jie Shi
4. Xiaoshuang Wang
5. Tong Li
6. Mengyao Xu
7. Xiaosu Chen
8. Yujia Zhao
9. Jiahao Han
10. Yongjun Piao
11. Wenwen Zhang
12. Pengpeng Qu
13. Longlong Wang
14. Rong Xiang
15. Yi Shi

• Curated by eLife

  Evaluation Summary:

  The authors studied ovarian carcinoma and identified a potential role of interleukin 20 receptor subunit alpha (IL20RA) and of IL-20 in regulating the transcoelomic metastasis of ovarian carcinoma, where IL-20 signaling in tumors is protective. This leads to the production of IL-18 and an M1 macrophage phenotype, with reduction of metastasis. The study is of interest to investigators in the area of cancer and cytokines and has potential therapeutic ramifications.

  (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

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

1. Rediet Zewdu
2. Elnaz Mirzaei Mehrabad
3. Kelley Ingram
4. Pengshu Fang
5. Katherine L. Gillis
6. Soledad A. Camolotto
7. Grace Orstad
8. Alex Jones
9. Michelle C. Mendoza
10. Benjamin T. Spike
11. Eric L. Snyder

• Curated by eLife

  Evaluation Summary:

  This manuscript greatly expands our understanding of an aggressive subtype of lung cancer. The author use in vivo cancer models and extensive analysis of the cancer cells states to uncover aspects of differentiation, drug responses and pathway activation. Findings of the study will help in the development of lineage-specific targeted therapies against cancers.

  (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, preLights

Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer

1. Yusuke Inoue
2. Ana Nikolic
3. Dylan Farnsworth
4. Alvin Liu
5. Marc Ladanyi
6. Romel Somwar
7. Marco Gallo
8. William W. Lockwood

• Curated by eLife

  Evaluation Summary:

  This manuscript will be of interest to cancer biologists studying cell fate transitions, particularly adenocarcinoma-to-small cell transitions that occur in prostate and lung cancer, which is a timely topic. While there is not a single linear mechanism identified that fully explains Kras-induced neuroendocrine cell fate suppression in all contexts, multiple new findings will likely be built upon by the field. Overall, the data are properly controlled and the key claims are supported.

  (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. All reviewers agreed to share their names with the authors.)

Reviewed by eLife

KSR1- and ERK-dependent Translational Regulation of the Epithelial-to-Mesenchymal Transition

1. Chaitra Rao
2. Danielle E. Frodyma
3. Siddesh Southekal
4. Robert A. Svoboda
5. Adrian R. Black
6. Chittibabu Guda
7. Tomohiro Mizutani
8. Hans Clevers
9. Keith R. Johnson
10. Kurt W. Fisher
11. Robert E. Lewis

• Curated by eLife

  Evaluation Summary:

  This paper demonstrates the involvement of Kinase Suppressor of Ras 1, a protein that acts as a scaffold in the mitogen activated protein kinase (MAPK) signaling cascade, in translational control of epithelial-to-mesenchymal transition. The analysis is thorough and includes both loss-of-function and gain-of-function studies. This study advances our understanding of cancer development.

  (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

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

1. Cara E Wogsland
2. Hilde E Lien
3. Line Pedersen
4. Pahul Hanjra
5. Sturla M Grondal
6. Rolf A Brekken
7. James B Lorens
8. Nils Halberg

Reviewed by Review Commons

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

1. Tomasz Radaszkiewicz
2. Michaela Nosková
3. Kristína Gömöryová
4. Olga Vondálová Blanářová
5. Katarzyna Anna Radaszkiewicz
6. Markéta Picková
7. Ráchel Víchová
8. Tomáš Gybeľ
9. Karol Kaiser
10. Lucia Demková
11. Lucia Kučerová
12. Tomáš Bárta
13. David Potěšil
14. Zbyněk Zdráhal
15. Karel Souček
16. Vítězslav Bryja

• Curated by eLife

  Evaluation Summary:

  Radaszkiewicz and collaborators describe RNF43 as a novel negative regulator of WNT5A-induced signaling in human cells. They demonstrate that RNF43 can interact with proteins in this pathway, namely ROR1, ROR2, VANGL1 and VANGL2. Specifically, they find that, through these interactions, RNF43 can suppress invasive properties of melanoma cells, as well as the development of resistance to BRAF V600E inhibitor. The experiments are well done and well explained; however, they were performed only in an in vitro setting and with a very limited number of cell lines.

  (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

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

1. Haritha Mathsyaraja
2. Jonathen Catchpole
3. Emily Eastwood
4. Ekaterina Babaeva
5. Michael Geuenich
6. Pei Feng Cheng
7. Brian Freie
8. Jessica Ayers
9. Ming Yu
10. Nan Wu
11. Kumud R Poudel
12. Amanda Koehne
13. William Grady
14. A McGarry Houghton
15. Yuzuru Shiio
16. David P MacPherson
17. Robert N Eisenman

• Curated by eLife

  Summary:

  The reviewers agreed that the paper provides strong in vivo data for a tumor-suppressive role for Mga in lung carcinogenesis. The authors convincingly show that MGA is important in oncogenesis. We note here that MGA is highly understudied (~200 publications) in and of itself despite its involvement with the MYC network for oncogenesis (~41,000 publications at the current time). Given a protein of 3000 amino acids, the number of potential protein partners and PTMs that might modify its tumor suppressor functions are staggering. However, the reviewers also noted that a previous paper has addressed the same topic and the novelty of the data presented here needs to be better explained and additional experiments are needed to strengthen and expand the new aspects.

  Reviewer #1 opted to reveal their name to the authors in the decision letter after review.

Reviewed by eLife