Cancer Biology

Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer

1. Tackhoon Kim
2. Byung-Sun Park
3. Soobeen Heo
4. Heeju Jeon
5. Jaeyeal Kim
6. Donghwa Kim
7. Sang Kook Lee
8. So-Youn Jung
9. Sun-Young Kong
10. Timothy Lu

• Curated by eLife

  eLife Assessment

  This study presents a valuable finding that synthetically lethal kinase genes FYN and KDM4 may play a role in drug resistance to kinase inhibitors in TNBC. The evidence supporting the claims of the authors is solid, although the exploration of the upstream mechanisms regulating KDM4A or the downstream pathways through which FYN upregulation confers drug resistance would have strengthened the study. The work will be of interest to medical biologists working in the field of breast cancer.

Reviewed by eLife

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells

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), they tried to uncover additional working mechanisms of citalopram in HCC treatment in the current study. The data here suggested 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

Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis

1. Zuzana Outla
2. Gizem Oyman-Eyrilmez
3. Katerina Korelova
4. Magdalena Prechova
5. Lukas Frick
6. Lenka Sarnova
7. Piyush Bisht
8. Petra Novotna
9. Jan Kosla
10. Patricia Bortel
11. Yasmin Borutzki
12. Andrea Bileck
13. Christopher Gerner
14. Mohammad Rahbari
15. Nuh Rahbari
16. Emrullah Birgin
17. Bibiana Kvasnicova
18. Andrea Galisova
19. Katerina Sulkova
20. Andreas Bauer
21. Njainday Jobe
22. Ondrej Tolde
23. Eva Sticova
24. Daniel Rösel
25. Tracy O'Connor
26. Martin Otahal
27. Daniel Jirak
28. Mathias Heikenwälder
29. Gerhard Wiche
30. Samuel M Meier-Menches
31. Martin Gregor

• Curated by eLife

  eLife Assessment

  This valuable study investigated the role of PLECTIN, a cytoskeletal crosslinker protein, in hepatocellular carcinoma development and progression. Using a liver-specific Plectin knockout mouse model, the authors showed solid evidence that PLECTIN is critical for hepatocarcinogenesis, since inhibition of PLECTIN suppressed tumor formation in multiple models. They also show that PLECTIN is key for HCC invasion and metastasis. They show a correlation between PLECTIN inhibition and attenuated FAK, MAPK/ERK, and PI3K/AKT signaling.

Reviewed by eLife

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

1. Jessica Armand
2. Sungsoo Kim
3. Kibum Kim
4. Eugene Son
5. Minah Kim
6. Hee Won Yang

• Curated by eLife

  eLife Assessment

  This study presents fundamental insights into overcoming resistance in hormone receptor-positive breast cancer by demonstrating that sustained CDK4/6 inhibitor treatment, either alone or in combination with CDK2 inhibitors, significantly suppresses the growth of drug-resistant cancer cells. The findings are supported by compelling evidence from both in vitro cell line experiments and in vivo mouse models, highlighting the therapeutic potential of maintaining CDK4/6 inhibitors beyond disease progression. Additionally, the identification of cyclin E overexpression as a key driver of resistance offers a target that will be of value for future therapeutic strategies, potentially improving outcomes for patients with advanced breast cancer.

Reviewed by eLife

Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning

1. Gabriella O Estevam
2. Edmond Linossi
3. Jingyou Rao
4. Christian B Macdonald
5. Ashraya Ravikumar
6. Karson M Chrispens
7. John A Capra
8. Willow Coyote-Maestas
9. Harold Pimentel
10. Eric A Collisson
11. Natalia Jura
12. James S Fraser

• Curated by eLife

  eLife Assessment

  This manuscript provides an important overview of potential resistance mutations within MET Receptor Tyrosine Kinase. The evidence supporting the findings is convincing - it should be pointed out that the approach is comparatively new for the application of protein kinases and the results are therefore of potentially great value. The results will be of value for clinicians facing drug resistance mutations, computational biologists who are training models of drug resistance mechanisms and biologists with an interest in cell signaling.

Reviewed by eLife

Non-destructive in situ monitoring of structural changes of 3D tumor spheroids during the formation, migration, and fusion process

1. Ke Ning
2. Yuanyuan Xie
3. Wen Sun
4. Lingke Feng
5. Can Fang
6. Rong Pan
7. Yan Li
8. Ling Yu

• Curated by eLife

  eLife Assessment

  The ingenious design in this study achieved the observation of 3D cell spheroids from an additional lateral view and gained more comprehensive information than the traditional one angle of imaging. This extended the methods to investigate cell behaviors in the growth or migration of tumor organoids in a time-lapse manner and these extensions should be important to the field. The authors provide compelling evidence that the methods work as described.

Reviewed by eLife

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. Tao Shi
7. Jie Shao
8. Lixia Yu
9. Baorui Liu
10. Yue Wang
11. Jia Wei

• 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

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

1. Jiadong Zhou
2. Xiao Albert Zhou
3. Li Hu
4. Yujie Ma
5. Jun Zhan
6. Zhanzhan Xu
7. Mei Zhou
8. Qinjian Shen
9. Zhaofei Liu
10. Shaohua Ma
11. Yuntao Xie
12. Jiadong Wang

• Curated by eLife

  eLife Assessment

  In this fundamental study, the authors describe ELF3 as a candidate driver of luminal progenitor transformation, such that its up-regulation during replicative stress conditions and in BRCA1 deficient cells may permit cell proliferation by suppressing genome instability. While the work is certainly of interest, the supporting data remain incomplete as luminal progenitor cells could not be isolated, which would be needed in order to definitively determine whether ELF3 is a driver of transformation in these cells. Overall this paper may offer insight into mechanisms by which BRCA1 deficiency fuels breast tumorigenesis.

Reviewed by eLife

Eliminating Aggressive Cancers via PROTAC-like Inducers of Ferroptosis

1. Avital Oknin-Vaisman
2. Deepanjan Panda
3. Rostislav Novak
4. Eliya Bitman-Lotan
5. Nikolett Pahor
6. Yamen Abu Ahmed
7. Guy Kamnesky
8. Markus E. Diefenbacher
9. Ashraf Brik
10. Amir Orian

Reviewed by Arcadia Science

Formation of malignant, metastatic small cell lung cancers through overproduction of cMYC protein in TP53 and RB1 depleted pulmonary neuroendocrine cells derived from human embryonic stem cells

1. Huanhuan Joyce Chen
2. Eric E Gardner
3. Yajas Shah
4. Kui Zhang
5. Abhimanyu Thakur
6. Chen Zhang
7. Olivier Elemento
8. Harold Varmus

• Curated by eLife

  eLife Assessment

  Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.

Reviewed by eLife