Cancer Biology

Bestrophin-4 relays Hes4 and interacts with Twist1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells

1. Zijing Wang
2. Bihan Xia
3. Shaochong Qi
4. Xian Zhang
5. Xiaoshuang Zhang
6. Yan Li
7. Huimin Wang
8. Miao Zhang
9. Ziyi Zhao
10. David Kerr
11. Li Yang
12. Shijie Cai
13. Jinlin Yang

• Curated by eLife

  eLife assessment

  The findings of this valuable manuscript advance our understanding of the significance of Bestrophin isoform 4 (BEST4) in suppressing colorectal cancer (CRC) progression. The authors used appropriate and validated methodology, such as the knockout of BEST4 using CRISPR/Cas9 in CRC cells, to provide a solid foundation for elucidating the potential link between BEST4 and CRC progression.

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Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor

1. Carolyn M Jablonowski
2. Waise Quarni
3. Shivendra Singh
4. Haiyan Tan
5. Dhanushka Hewa Bostanthirige
6. Hongjian Jin
7. Jie Fang
8. Ti-Cheng Chang
9. David Finkelstein
10. Ji-Hoon Cho
11. Dongli Hu
12. Vishwajeeth Pagala
13. Sadie Miki Sakurada
14. Shondra M Pruett-Miller
15. Ruoning Wang
16. Andrew Murphy
17. Kevin Freeman
18. Junmin Peng
19. Andrew M Davidoff
20. Gang Wu
21. Jun Yang

• Curated by eLife

  eLife assessment

  This important study reports on key characteristics of MYC-driven cancers: dysregulated pre-mRNA splicing and altered metabolism, with the data being overall solid. The manuscript should be of broad interest to cancer biologists due to its therapeutic implications.

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Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction

1. Sara Latini
2. Veronica Venafra
3. Giorgia Massacci
4. Valeria Bica
5. Simone Graziosi
6. Giusj Monia Pugliese
7. Marta Iannuccelli
8. Filippo Frioni
9. Gessica Minnella
10. John Donald Marra
11. Patrizia Chiusolo
12. Gerardo Pepe
13. Manuela Helmer Citterich
14. Dimitros Mougiakakos
15. Martin Böttcher
16. Thomas Fischer
17. Livia Perfetto
18. Francesca Sacco

• Curated by eLife

  eLife assessment

  This important study could potentially represent a step forward towards personalized medicine by combining cell-based data and a prior-knowledge network to derive Boolean-based predictive logic models to uncover altered protein/signaling networks within cancer cells. The level of evidence supporting the conclusions is solid, as the authors present analyses on independent, real-world data to validate their approach. These findings could be of interest to medical biologists working in the field of cancer, as the work should inform drug development and treatment choices in the field of oncology.

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Replication stress inducing ELF3 upregulation promotes BRCA1-deficient breast tumorigenesis in luminal progenitors

• Curated by eLife

  eLife assessment

  This important study reveals ELF3 as a putative candidate driver of luminal progenitor (LP) transformation. Up-regulation of ELF3 during replicative stress conditions and in BRCA1 deficient cells may permit cell proliferation by suppressing genome instability. While the hypothesis is compelling, the experimental support is still incomplete, as it does not adequately demonstrate the role of ELF3 in LP cells per se. The mechanistic underpinnings by which ELF3 promotes cell tolerance to DNA damage were not fully explored either. With improvements, the work has the potential to enhance our understanding of how BRCA1 deficiency fuels LP transformation and thereby breast tumorigenesis.

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Ribosome subunit attrition and activation of the p53–MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

1. Gregory Caleb Howard
2. Jing Wang
3. Kristie L Rose
4. Camden Jones
5. Purvi Patel
6. Tina Tsui
7. Andrea C Florian
8. Logan Vlach
9. Shelly L Lorey
10. Brian C Grieb
11. Brianna N Smith
12. Macey J Slota
13. Elizabeth M Reynolds
14. Soumita Goswami
15. Michael R Savona
16. Frank M Mason
17. Taekyu Lee
18. Stephen Fesik
19. Qi Liu
20. William P Tansey

• Curated by eLife

  eLife assessment

  This important paper reveals that one of the major roles of the WDR5 WIN site is to promote ribosome synthesis, and that by attacking the WIN site with inhibitors ribosome attrition occurs creating new vulnerabilities that can be therapeutically exploited. This deficiency of ribosomal proteins also provokes the p53 response. The data from a variety of approaches is generally very convincing, and together buttresses the authors' conclusions and interpretations quite nicely; overall, this paper will provide a justification for pre-clinical and translational studies of WDR5 interaction site inhibitors.

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Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer

1. Yi Ban
2. Yue Zou
3. Sharrell B. Lee
4. Robert B.Bednarczyk
5. Jianting Sheng
6. Yuliang Cao
7. Stephen T. C. Wong
8. Dingcheng Gao

• Curated by eLife

  eLife assessment

  This valuable study used a modified PyMT model to investigate whether increased rRNA synthesis provides a therapeutic opportunity to target chemoresistance. The evidence supporting the claims of the authors is solid, although the use of a more rigorous approach to capture all the relevant events during the EMT process would have strengthened the study. The work will be of interest to clinicians or cancer biologists.

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Dynamic analysis of circulating tumor DNA to predict the prognosis and monitor the treatment response of patients with metastatic triple-negative breast cancer: A prospective study

1. Yajing Chi
2. Mu Su
3. Dongdong Zhou
4. Fangchao Zheng
5. Baoxuan Zhang
6. Ling Qiang
7. Guohua Ren
8. Lihua Song
9. Bing Bu
10. Shu Fang
11. Bo Yu
12. Jinxing Zhou
13. Jinming Yu
14. Huihui Li

• Curated by eLife

  eLife assessment

  This prospective study advances our understanding of the predictive role of circulating tumor DNA (ctDNA) in the prognosis and of patients with mTNBC as well as other cancers. The evidence supporting the conclusions is convincing with rigorous analysis of the association between ctDNA (ctDNA-positive or not) with the progression-free survival (PFS) of patients. However, there are a few areas in which the article may be improved through further analysis of the clinical outcome and elaboration of the prospective study (i.e., the inclusion and exclusion criteria of the patients). The work will be of broad interest to clinicians, medical researchers and scientists working in cancers.

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Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study

1. Guanglei Chen
2. Xi Gu
3. Jinqi Xue
4. Xu Zhang
5. Xiaopeng Yu
6. Yu Zhang
7. Ailin Li
8. Yi Zhao
9. Guijin He
10. Meiyue Tang
11. Fei Xing
12. Jianqiao Yin
13. Xiaobo Bian
14. Ye Han
15. Shuo Cao
16. Chao Liu
17. Xiaofan Jiang
18. Keliang Zhang
19. Yan Xia
20. Huajun Li
21. Nan Niu
22. Caigang Liu
23. On behalf of the Northeastern Clinical Research Alliance of Oncology (NCRAO)

• Curated by eLife

  eLife assessment

  This study presents a valuable finding of a novel combinatory regimen which integrate immunotherapy, radiotherapy and chemotherapy in the current refractory triple negative breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples would have strengthened the study. The work will be of interest to Clinicians working on breast cancer.

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Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts

1. Weirong Kang
2. Yibo Fan
3. Yinxiao Du
4. Elina A. Tonkova
5. Yi-Hsin Hsu
6. Kel Vin Tan
7. Stephanie Alexander
8. Bin Sheng Wong
9. Haocheng Yang
10. Jingyuan Luo
11. Kuo Yao
12. Jiayao Yang
13. Xin Hu
14. Tingting Liu
15. Yu Gan
16. Jian Zhang
17. Jean J. Zhao
18. Konstantinos Konstantopoulos
19. Peter Friedl
20. Pek Lan Khong
21. Aiping Lu
22. Mien-Chie Hung
23. Michael B. Brenner
24. Jeffrey E. Segall
25. Zhizhan Gu

• Curated by eLife

  eLife assessment

  This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.

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SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells

1. Linda Zhang
2. Joanne I. Hsu
3. Etienne D. Braekeleer
4. Chun-Wei Chen
5. Tajhal D. Patel
6. Alejandra G. Martell
7. Anna G. Guzman
8. Katharina Wohlan
9. Sarah M. Waldvogel
10. Hidetaka Urya
11. Ayala Tovy
12. Elsa Callen
13. Rebecca Murdaugh
14. Rosemary Richard
15. Sandra Jansen
16. Lisenka Vissers
17. Bert B.A. de Vries
18. Andre Nussenzweig
19. Shixia Huang
20. Cristian Coarfa
21. Jamie N. Anastas
22. Koichi Takahashi
23. George Vassiliou
24. Margaret A. Goodell

• Curated by eLife

  eLife assessment

  Gain-of-function mutations and amplifications of PPM1D are found across several human cancers and are associated with advanced tumor stage and worse prognosis. Thus far, the clinical translation has not been possible due to the lack of PPM1D inhibitors with favorable pharmacokinetic properties. This useful study leverages CRISPR/Cas9 screening to determine that loss of SOD1 and is synthetic lethal with PPM1D mutation in leukemia. The mechanistic analyses at still incomplete.

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Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues

1. Wanyoung Lim
2. Inwoo Hwang
3. Jiande Zhang
4. Zhenzhong Chen
5. Jeonghun Han
6. Jaehyung Jeon
7. Bon-Kyoung Koo
8. Sangmin Kim
9. Jeong Eon Lee
10. Youngkwan Kim
11. Kenneth J Pienta
12. Sarah R Amend
13. Robert H Austin
14. Jee-Yin Ahn
15. Sungsu Park

• Curated by eLife

  eLife assessment

  This study based on the use of Cancer Drug Resistance Accelerator (CDRA) chip is valuable as a platform technology to assess chemoresistance mechanisms. The strength is convincing from the technological point of view. However, the use of a single cell line model is a limitation. However we acknowledge the authors' plan to further validate their current findings across multiple TNBC cell lines.

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DePARylation is critical for S phase progression and cell survival

1. Litong Nie
2. Chao Wang
3. Min Huang
4. Xiaoguang Liu
5. Xu Feng
6. Mengfan Tang
7. Siting Li
8. Qinglei Hang
9. Hongqi Teng
10. Xi Shen
11. Li Ma
12. Boyi Gan
13. Junjie Chen

• Curated by eLife

  eLife assessment

  The demonstration that the PARG dePARylation enzyme is required in S phase to remove polyADP-ribose (PAR) protein adducts that are generated in response to the presence of unligated Okazaki fragments is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARP1-mediated PARylation and PARG-catalyzed dePARylation in S-phase progression.

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Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma

1. Dan-Dan Zou
2. Ya-Zhou Sun
3. Xin-Jie Li
4. Wen-Juan Wu
5. Dan Xu
6. Yu-Tong He
7. Jue Qi
8. Ying Tu
9. Yang Tang
10. Yun-Hua Tu
11. Xiao-Li Wang
12. Xing Li
13. Feng-Yan Lu
14. Ling Huang
15. Heng Long
16. Li He
17. Xin Li

• Curated by eLife

  eLife assessment

  This important study delineates the molecular changes driving the progression from actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC). Using state-of-the-art single-cell RNA profiling of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, thus covering comprehensive clinical courses of cSCC, the authors provide an invaluable data resource. This study identified several previously unreported and interesting candidate genes involved in different stages of the malignant progression of skin neoplasias, which have been validated in situ, and partially in vitro. Although data analysis needs improvement and comparison to other published data sets to fully support the claims and conclusions, these findings substantially advance our understanding of the molecular changes leading to skin cancer.

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Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics

1. Timothy J Walker
2. Eduardo Reyes-Alvarez
3. Brandy D Hyndman
4. Michael G Sugiyama
5. Larissa CB Oliveira
6. Aisha N Rekab
7. Mathieu JF Crupi
8. Rebecca Cabral-Dias
9. Qianjin Guo
10. Patricia LM Dahia
11. Douglas S Richardson
12. Costin N Antonescu
13. Lois M Mulligan

• Curated by eLife

  eLife assessment

  This valuable paper provides convincing evidence that loss of the tumor suppressor TMEM127 causes disorganization of plasma membrane lipid domains, alters clathrin assembly, and inhibits endocytosis of a variety of cell surface receptors, leading to increased cell surface levels of signaling proteins including RET and other transmembrane receptor tyrosine kinases. The results are significant for understanding how RET127 loss contributes to pheochromocytoma, although the evidence is indirect owing to the lack of human pheochromocytoma cell lines. The results will be of interest for researchers studying pheochromocytoma and endocytosis mechanisms.

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Molecular classification and tumor microenvironment characteristics in pheochromocytomas

1. Sen Qin
2. Yawei Xu
3. Shimiao Yu
4. Wencong Han
5. Shiheng Fan
6. Wenxiang Ai
7. Kenan Zhang
8. Yizhou Wang
9. Xuehong Zhou
10. Qi Shen
11. Kan Gong
12. Luyang Sun
13. Zheng Zhang

• Curated by eLife

  eLife assessment

  This valuable study advances our understanding of the potential therapeutic strategies for the treatment of pheochromocytomas using single-cell transcriptomics. The authors propose a new molecular classification criterion based on the characterization of tumor microenvironmental features, based on solid evidence. The work, which could be improved further through delineating the choice of the PASS scoring system, will be of broad interest to clinicians, medical researchers, and scientists working in the field of pheochromocytoma.

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DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers

1. Jose Mario Bello Pineda
2. Robert K. Bradley

• Curated by eLife

  eLife assessment

  This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. Compared to an earlier version, the quality of the manuscript has been enhanced, for example Figure 5 now illustrates the key features of survival probability estimates over time for patients assigned to with the test or training set.

Reviewed by eLife

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers

1. Jose Mario Bello Pineda
2. Robert K. Bradley

• Curated by eLife

  eLife assessment

  This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. Compared to an earlier version, the quality of the manuscript has been enhanced, for example Figure 5 now illustrates the key features of survival probability estimates over time for patients assigned to with the test or training set.

Reviewed by eLife

Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2

1. Fan Sun
2. Pengrong Yan
3. Yadong Xiao
4. Hongqiao Zhang
5. Steven D. Shapiro
6. Gutian Xiao
7. Zhaoxia Qu

• Curated by eLife

  eLife assessment

  This study presents a valuable finding for the immunotherapy of cancer. The data support the role of PDLIM2 as a tumor suppressor, and more immediately, its relevance for strategies to improve the efficacy of immunotherapy. The evidence supporting the conclusions is compelling and the work will be of interest to biomedical scientists working on cancer immunology.

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Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

1. Jing Xie
2. Yafei Xu
3. Xuhua Liu
4. Li Long
5. Ji Chen
6. Chunyan Huang
7. Yan Shao
8. Zhiqing Cai
9. Zhimin Zhang
10. Ruixin Zhou
11. Jiarong Leng
12. Xiaochun Bai
13. Qiancheng Song

• Curated by eLife

  eLife assessment

  This is an important study, that adds to the field a new understanding of exercise or mechanical loading, microRNAs, and secreted extracellular vessicles in the field of lung cancer (NSCLC), which may have relevance to other osteolytic cancers. The strength of the evidence was mixed: whereas in vitro microRNA experiments were convincing, other elements were incomplete (e.g., proving the roles of osteocytes, as opposed to other mechanosensitive cells, in vivo). This work would be of broad interest to those investigating osteolytic cancers, and the role of exercise in bone cancer, preclinically.

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Complementary CRISPR screen highlights the contrasting role of membrane-bound and soluble ICAM-1 in regulating antigen-specific tumor cell killing by cytotoxic T cells

1. Ann-Kathrin Herzfeldt
2. Marta Puig Gamez
3. Eva Martin
4. Lukasz Miloslaw Boryn
5. Praveen Baskaran
6. Heinrich J Huber
7. Michael Schuler
8. John E Park
9. Lee Kim Swee

• Curated by eLife

  eLife assessment

  This important research uses complementary CRISPR screening strategies to reveal novel pathways that prevent T cells from killing tumor cells. The evidence presented to support the claims is solid, although some additional assays defining the features of these novel pathways and their clinical relevance are still required. Overall, this work will be of broad interest to immunologists, cancer biologists, and those interested in cell adhesion and cell-cell communication.

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