DataVXAdvanced SciencePaper
journal article·2025-04Open access

Tribbles Pseudokinase 3 Converts Sorafenib Therapy to Neutrophil‐Mediated Lung Metastasis in Hepatocellular Carcinoma

Xu‐Yan Wang, Yuan Liao, Rui‐Qi Wang, Yi‐Tong Lu, Ying‐Zhe Wang, Yu‐Qi Xin, Dong‐Ming Kuang, Xiang‐Ming Lao, Junying Xu, Zhi‐Ling Zhou, Kunhua Hu

Advanced Science· Volume 12· Issue 13
Publisher pageOpen full text
Source abstract

Abstract

Abstract Rapid development of resistance to sorafenib and subsequent hyperprogression in patients with advanced hepatocellular carcinoma (HCC) pose significant challenges, with the underlying mechanisms still largely unknown. Herein, sorafenib‐induced TRIB3 is identified as a liver‐specific determinant driving secondary resistance to sorafenib by facilitating the accumulation of protumorigenic neutrophils within tumors. Mechanistically, TRIB3, triggered by the sorafenib‐elicited ROS‐ER stress axis, operates in an NF‐κB‐dependent manner to upregulate CXCR1/2 ligands, subsequently promoting neutrophil recruitment into tumors. These enriched neutrophils enhance epithelial‐mesenchymal transition processes in malignant cells through the oncostatin M‐STAT3 pathway, thereby repurposing the therapeutic efficacy of sorafenib away from anti‐angiogenesis and toward lung metastasis. Clinically, elevated TRIB3 expression indicates inferior survival and unfavorable clinical efficacy of sorafenib in HCC patients. Correspondingly, strategies that either inhibiting TRIB3 upregulation or blocking its downstream signaling successfully augment the therapeutic efficacy of sorafenib and prevent sorafenib‐induced hyperprogression in vivo. The study thus identifies a pivotal mechanism of sorafenib resistance in HCC, centered on the TRIB3‐mediated recruitment of protumorigenic neutrophils and subsequent disease hyperprogression.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Endoplasmic Reticulum Stress and Disease · Phagocytosis and Immune Regulation · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Guangdong Provincial Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou 510630 China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 China

Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment (No. 2021B1212040004) Zhuhai Institute of Translational Medicine Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University) Zhuhai 519000 China

Department of Laboratory Medicine The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou 510630 China

Department of Pharmacy Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University) Zhuhai 519000 China

School of Life Sciences Sun Yat‐sen University Guangzhou 510275 China

Department of Oncology The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Nanjing Medical University Wuxi 214023 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province · Fundamental Research Funds for the Central Universities

References (46)

Show source-provided references
1. 10.3390/ijms2307377810.3390/ijms23073778 ↗
2. 10.1038/s41575-019-0229-410.1038/s41575-019-0229-4 ↗
3. 10.1016/j.ymthe.2022.09.01910.1016/j.ymthe.2022.09.019 ↗
4. 10.1038/s41467-024-46835-210.1038/s41467-024-46835-2 ↗
5. 10.1172/JCI7438110.1172/JCI74381 ↗
6. 10.1038/s41575-022-00704-910.1038/s41575-022-00704-9 ↗
7. 10.3748/wjg.v29.i10.155110.3748/wjg.v29.i10.1551 ↗
8. 10.1158/0008-5472.CAN-04-144310.1158/0008-5472.CAN-04-1443 ↗
9. 10.1053/j.seminoncol.2012.05.00510.1053/j.seminoncol.2012.05.005 ↗
10. 10.1056/NEJMoa070885710.1056/NEJMoa0708857 ↗
11. 10.1016/S1470-2045(08)70285-710.1016/S1470-2045(08)70285-7 ↗
12. 10.1016/j.jhep.2012.06.01410.1016/j.jhep.2012.06.014 ↗
13. 10.1016/j.canlet.2012.10.02110.1016/j.canlet.2012.10.021 ↗
14. 10.1158/0008-5472.CAN-23-179610.1158/0008-5472.CAN-23-1796 ↗
15. 10.1634/theoncologist.2013-040910.1634/theoncologist.2013-0409 ↗
16. Hendrixson M. · Med. Sci. (Basel) · 2024 · 12 · 20
17. 10.1007/s00280-022-04428-010.1007/s00280-022-04428-0 ↗
18. 10.1074/jbc.M40773220010.1074/jbc.M407732200 ↗
19. 10.1016/j.tcb.2016.11.00210.1016/j.tcb.2016.11.002 ↗
20. 10.3390/cancers1318451710.3390/cancers13184517 ↗
21. 10.1038/sj.onc.120636710.1038/sj.onc.1206367 ↗
22. 10.1126/scitranslmed.abf099210.1126/scitranslmed.abf0992 ↗
23. 10.1038/s41467-020-17385-010.1038/s41467-020-17385-0 ↗
24. 10.1073/pnas.210159211810.1073/pnas.2101592118 ↗
25. 10.7150/thno.4592410.7150/thno.45924 ↗
26. 10.1038/s41467-020-20107-110.1038/s41467-020-20107-1 ↗
27. 10.1038/s41392-023-01570-w10.1038/s41392-023-01570-w ↗
28. 10.1038/sj.emboj.760059610.1038/sj.emboj.7600596 ↗
29. 10.1002/hep.2825110.1002/hep.28251 ↗
30. 10.1038/s41401-020-0478-310.1038/s41401-020-0478-3 ↗
31. 10.3389/fimmu.2020.0125910.3389/fimmu.2020.01259 ↗
32. 10.1038/s41423-020-0412-010.1038/s41423-020-0412-0 ↗
33. 10.1038/s41417-021-00303-x10.1038/s41417-021-00303-x ↗
34. 10.1038/sj.onc.120526010.1038/sj.onc.1205260 ↗
35. 10.1038/srep1766310.1038/srep17663 ↗
36. 10.3390/cells901021710.3390/cells9010217 ↗
37. 10.1038/s41590-018-0044-z10.1038/s41590-018-0044-z ↗
38. 10.1038/s41698-018-0048-z10.1038/s41698-018-0048-z ↗
39. 10.3390/ijms24141147110.3390/ijms241411471 ↗
40. 10.4049/jimmunol.181.5.308910.4049/jimmunol.181.5.3089 ↗
41. 10.1016/j.immuni.2022.11.01410.1016/j.immuni.2022.11.014 ↗
42. 10.1038/s41586-022-05400-x10.1038/s41586-022-05400-x ↗
43. 10.1016/j.jhep.2010.08.04110.1016/j.jhep.2010.08.041 ↗
44. 10.1038/s41419-024-06472-510.1038/s41419-024-06472-5 ↗
45. 10.1016/j.ccell.2024.10.01210.1016/j.ccell.2024.10.012 ↗
46. 10.1002/hep.2329110.1002/hep.23291 ↗