Clinical and translational medicine · 2026
STK25 inhibits cancer-associated fibroblast activation to overcome cetuximab resistance in colorectal cancer.
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Hou Yifan, Chen Jiangbo, Hao Hao, Song Tongkun, Song Lin, Xing Pu, Weng Kai, Ran Yumeng, Yang Xinying, Qiao Xiaowen, Chen Jie, Yao Ruibin, Yang Hong, Chen Lei, Di Jiabo, Xu Kai, Su Xiangqian, Jiang Beihai
Аннотация
BACKGROUND: Cancer-associated fibroblasts (CAFs) within the tumour microenvironment play a pivotal role in colorectal cancer (CRC) progression and therapeutic resistance. Serine/threonine protein kinase 25 (STK25) exerts multiple roles in tumourigenesis; however, its role in mediating tumour-stroma crosstalk remains largely unexplored.
METHODS: Primary CAFs were isolated from CRC patient tissues and characterised to confirm their identity. The effects of STK25 expression on CAF activity and CAF-mediated tumour progression were evaluated both in vitro and in vivo. Western blot, qRT-PCR, ChIP and dual-luciferase reporter assays were performed to elucidate the mechanism by which STK25 regulated CAF activation. Moreover, the effect of STK25 expression on CAF-induced cetuximab resistance was assessed in vitro and in vivo. The clinical significance of STK25 expression was determined in CRC patient tissues, tissue microarrays and patient-derived organoids.
RESULTS: Knockdown of STK25 in CRC cells enhanced CAF proliferation, migration and activation, whereas its overexpression exhibited the opposite effect. STK25-knockdown-mediated CAF activation subsequently promoted CRC cell proliferation and metastasis. Moreover, STK25 depletion combined with CAFs significantly enhanced CRC tumour growth in vivo. Mechanistically, STK25 deficiency activated the NF-κB pathway, leading to p50 phosphorylation which directly bound to the AREG promoter, thereby transcriptionally up-regulating AREG expression. In addition, STK25-regulated AREG/EGFR axis mediated the crosstalk between CRC cells and CAFs. More importantly, CAFs conferred resistance to the anti-EGFR antibody cetuximab, which could be reversed either by STK25 overexpression or by AREG-neutralising antibody treatment. Clinically, low STK25 expression correlated with elevated CAFs marker levels and poor cetuximab response in CRC patients.
CONCLUSIONS: Our findings identified STK25 as a critical regulator of the NF-κB/AREG/EGFR axis in tumour-CAF communication and highlight its potential as a therapeutic target for overcoming CAF-induced cetuximab resistance in CRC.
KEY POINTS: STK25 deficiency enhanced CAF-mediated CRC growth via the NF-κB/AREG/EGFR axis. STK25 overexpression or AREG antibody overcame CAF-mediated cetuximab resistance. CRC patients with high STK25 and low CAFs marker levels might benefit from cetuximab treatment.
METHODS: Primary CAFs were isolated from CRC patient tissues and characterised to confirm their identity. The effects of STK25 expression on CAF activity and CAF-mediated tumour progression were evaluated both in vitro and in vivo. Western blot, qRT-PCR, ChIP and dual-luciferase reporter assays were performed to elucidate the mechanism by which STK25 regulated CAF activation. Moreover, the effect of STK25 expression on CAF-induced cetuximab resistance was assessed in vitro and in vivo. The clinical significance of STK25 expression was determined in CRC patient tissues, tissue microarrays and patient-derived organoids.
RESULTS: Knockdown of STK25 in CRC cells enhanced CAF proliferation, migration and activation, whereas its overexpression exhibited the opposite effect. STK25-knockdown-mediated CAF activation subsequently promoted CRC cell proliferation and metastasis. Moreover, STK25 depletion combined with CAFs significantly enhanced CRC tumour growth in vivo. Mechanistically, STK25 deficiency activated the NF-κB pathway, leading to p50 phosphorylation which directly bound to the AREG promoter, thereby transcriptionally up-regulating AREG expression. In addition, STK25-regulated AREG/EGFR axis mediated the crosstalk between CRC cells and CAFs. More importantly, CAFs conferred resistance to the anti-EGFR antibody cetuximab, which could be reversed either by STK25 overexpression or by AREG-neutralising antibody treatment. Clinically, low STK25 expression correlated with elevated CAFs marker levels and poor cetuximab response in CRC patients.
CONCLUSIONS: Our findings identified STK25 as a critical regulator of the NF-κB/AREG/EGFR axis in tumour-CAF communication and highlight its potential as a therapeutic target for overcoming CAF-induced cetuximab resistance in CRC.
KEY POINTS: STK25 deficiency enhanced CAF-mediated CRC growth via the NF-κB/AREG/EGFR axis. STK25 overexpression or AREG antibody overcame CAF-mediated cetuximab resistance. CRC patients with high STK25 and low CAFs marker levels might benefit from cetuximab treatment.