Cancer Biology

Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer

1. Yue Zhang
2. Hanbing Wang
3. Yutao Wei
4. Yunfeng Pan
5. Xueru Song
6. Jie Shao
7. Lixia Yu
8. Tao Shi
9. Yue Wang

• Curated by eLife

  eLife Assessment

  Based on the perceived low efficacy of current therapies targeted to FGFR2 in gastric cancer (GC), the authors investigate an approach which combines SHP2 inhibition with existing FGFR2 inhibitors. The data were largely collected and analysed using solid and validated methodology. There is some useful data regarding combination therapy in a new clinical cohort, which supports previous studies that have reported the potential of targeting RTKs together with phosphatases.

Reviewed by eLife

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

1. David Papadopoli
2. Ranveer Palia
3. Predrag Jovanovic
4. Sébastien Tabariès
5. Emma Ciccolini
6. Valerie Sabourin
7. Sebastian Igelmann
8. Shannon McLaughlan
9. Lesley Zhan
10. HaEun Kim
11. Nabila Chekkal
12. Krzysztof J Szkop
13. Thierry Bertomeu
14. Jibin Zeng
15. Julia Vassalakis
16. Farzaneh Afzali
17. Slim Mzoughi
18. Ernesto Guccione
19. Mike Tyers
20. Daina Avizonis
21. Ola Larsson
22. Lynne-Marie Postovit
23. Sergej Djuranovic
24. Josie Ursini-Siegel
25. Peter M Siegel
26. Michael Pollak
27. Ivan Topisirovic

• Curated by eLife

  eLife Assessment

  The authors present an important set of data implicating ETFDH as an epigenetically suppressed gene in cancer with tumor suppressive functions. The evidence is convincing, with the authors demonstrating that suppression of ETFDH activity results in accumulation of amino acids that impact metabolism via hyperactive mTORC1.

Reviewed by eLife

The DBD-α4 helix of EWSR1::FLI1 is required for GGAA microsatellite binding that underlies genome regulation in Ewing sarcoma

1. Ariunaa Bayanjargal
2. Cenny Taslim
3. Iftekhar A Showpnil
4. Julia Selich-Anderson
5. Jesse C Crow
6. Runwei Zhou
7. Stephen L Lessnick
8. Emily Rose Theisen

• Curated by eLife

  eLife Assessment

  This paper investigates the Achilles' heel of an aggressive pediatric bone cancer known as Ewing sarcoma. The authors aimed to better understand how its previously undruggable drivers mediate oncogenic mechanisms using several omics approaches. Transcriptomic changes aligned with their findings provide convincing evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable new insights into the underlying oncogenic mechanisms in Ewing sarcoma.

Reviewed by eLife

Depletion of rRNA Methyltranferase METTL5 Enhances Anti-Tumor Immune Response via Neoantigen Generated from Cryptic Translation

1. Yangyi Zhang
2. Xiaoyan Shi
3. Yuci Wang
4. Ruiqi Wang
5. Folan Lin
6. Yanlan Cao
7. Wanqiu Li
8. Hao Chen

• Curated by eLife

  eLife Assessment

  This study presents a valuable finding that depletion of the rRNA methyltransferase METTL5 enhances anti-tumor immunity through a novel mechanism involving neoantigen generation from non-canonical translation. The evidence supporting the central conclusions is solid, with comprehensive multi-omics data including ribosome profiling, immunopeptidomics, TCR sequencing, and multiple in vivo tumor models demonstrating synergy with immune checkpoint blockade.

Reviewed by eLife

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs

1. Fangyuan Dong
2. Shan Zhang
3. Kaiyuan Song
4. Luju Jiang
5. Li-Peng Hu
6. Qing Li
7. Xue-Li Zhang
8. Jun Li
9. Mingxuan Feng
10. Zhi-Wei Cai
11. Hong-Fei Yao
12. Rong-Kun Li
13. Hui Li
14. Jie Chen
15. Xiaona Hu
16. Jiaofeng Wang
17. Chongyi Jiang
18. Helen He Zhu
19. Cun Wang
20. Lin-Tai Da
21. Zhi-Gang Zhang
22. Zhijun Bao
23. Xu Wang
24. Shu-Heng Jiang

• Curated by eLife

  eLife Assessment

  This important study provides solid evidence to support the anti-tumor potential of citalopram, originally an anti-depression drug, in hepatocellular carcinoma (HCC). In addition to their previous report on directly targeting tumor cells via glucose transporter 1 (GLUT1), the authors tried to uncover additional working mechanisms of citalopram in HCC treatment in the current study. The data here suggests that citalopram may regulate the phagocytotic function of TAM via C5aR1 or CD8+T cell function to suppress HCC growth in vivo.

Reviewed by eLife

PTEN restrains SHH medulloblastoma growth through cell autonomous and nonautonomous mechanisms

1. Zhimin Lao
2. Salsabiel El Nagar
3. Yinwen Liang
4. Daniel Stephen
5. Alexandra L Joyner

• Curated by eLife

  eLife Assessment

  This valuable study provides insights into the role of Pten mutations in SHH-medulloblastoma, by using mouse models to resolve the effects of heterozygous vs homozygous mutations on proliferation and cell death throughout tumorigenesis. The experiments presented are convincing, with rigorous quantifications and orthogonal experimentation provided throughout, and the models employing sporadic oncogene induction, rather than EGL-wide genetic modifications, represent an advancement in experimental design. However, additional experimentation focused on a greater characterization of macrophage phenotypes (e.g., microglia vs circulating monocytes) would enhance this study. The work will be of interest to medical biologists studying general cancer mechanisms, as the function of Pten may be similar across tumor types.

Reviewed by eLife

Myosin VI orchestrates estrogen-driven gene expression in breast cancer cells

1. Yukti Hari-Gupta
2. Danielle Lambert
3. Isabel W. Shahid-Fuente
4. Natalia Fili
5. Ália dos Santos
6. Alexandria Sprules
7. Hyejeong Rosemary Kim
8. Alexander W. Cook
9. Peter J.I. Ellis
10. Jesse Aaron
11. Teng-Leong Chew
12. Lin Wang
13. Christopher P. Toseland

Reviewed by PREreview

Identifying tissue states by spatial protein patterns related to chemotherapy response in triple-negative breast cancer

1. Luciana M Luque
2. Mohammad Asif Khan
3. Giuseppe Torrisi
4. Tessa D Green
5. David Hardman
6. Claudia Owczarek
7. Tom A Phillips
8. Debora S Marks
9. Maddy Parsons
10. Chris Sander
11. Linus J Schumacher

• Curated by eLife

  eLife Assessment

  This is an important work implementing data mining methods on IMC data to discover spatial protein patterns related to the triple-negative breast cancer patients' chemotherapy response. The evidence supporting the claims of the authors is solid, although more detailed methodology clarification and validation are needed. While the accuracy of the methods is not very high, the work shows potential for translational application.

Reviewed by eLife

Molecular and Functional Analysis of Calcium Binding by a Cancer-linked Calreticulin Mutant

1. Ishmael Nii Ayibontey Tagoe
2. Amanpreet Kaur
3. Osbourne Quaye
4. Emmanuel Ayitey Tagoe
5. Nicole Koropatkin
6. Leslie S Satin
7. Malini Raghavan

• Curated by eLife

  eLife Assessment

  This study investigates low-affinity Ca2+ binding by WT calreticulin and mutant calreticulin associated with type I myeloproliferative neoplasms, as well as the impact on Ca2+ fluxes in suspension cultures of megakaryocyte-like cells in vitro in response to ER Ca2+ ATPase inhibitors that deplete endoplasmic reticulum (ER) Ca2+ store and open plasma membrane Ca2+ channels through STIM1-Orai interactions. The results are important in that they show that Ca2+ binding by calreticulin and store-operated Ca2+ entry are not fundamentally impacted by the type I deletion mutation in calreticulin, which rules out a direct effect of the calreticulin mutation on its own low-affinity Ca2+ binding and any broad impact on ER Ca2+ regulation. The strength of the data and methods used ranges from solid to convincing, although the use of suspension-based flow cytometric assays to investigate ER Ca2+ levels and Ca2+ entry can be challenged. High-affinity Ca2+ binding sites could be further considered, and possible confounding effects of Abl kinase activity in the megakaryocyte-like cell lines could be offset.

Reviewed by eLife

RAB14-dependent tubulovesicular recycling directs MET to invadopodia, promoting TNBC cell invasion

1. Amrita Khamari
2. Atreyee Guria
3. Kiran Tak
4. Rajiv Sharma
5. Yannis Kalaidzidis
6. Sunando Datta

• Curated by eLife

  eLife Assessment

  This valuable paper advances understanding of the role of the HGF receptor, MET, in cancer cell invasion by demonstrating HGF-induced coordinated trafficking of MET and metalloprotease MT1-MMP into invadopodia. The results are generally solid, but there are concerns about the cell biology and whether the trafficking mechanism is clinically relevant. It's also unclear whether this is a general mechanism or specific to triple-negative breast cancer cells. The paper will be of interest to cancer cell biologists.

Reviewed by eLife