Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer

被引：0

作者：

He, Jiahua ^{[1
]}

Li, Weihao ^{[1
]}

Wang, Song ^{[1
]}

Lan, Jin ^{[1
]}

Hong, Xuanlin ^{[2
]}

Liao, Leen ^{[1
]}

Kang, Da ^{[1
]}

Wang, Weifeng ^{[1
]}

Wang, Ruowei ^{[1
]}

Zhang, Weili ^{[1
]}

Yu, Long ^{[1
]}

Ou, Qingjian ^{[1
]}

Fang, Yujing ^{[1
]}

Wu, Xiaojun ^{[1
]}

Lin, Junzhong ^{[1
]}

Ding, Peirong ^{[1
,3
]}

Zhou, Chi ^{[1
,3
]}

Pan, Zhizhong ^{[1
,3
]}

Peng, Jianhong ^{[1
,3
]}

机构：

[1] Sun Yat sen Univ, Guangdong Prov Clin Res Ctr Canc, Dept Colorectal Surg, State Key Lab Oncol South China,Canc Ctr, Guangzhou, Guangdong, Peoples R China

[2] Shaoguan Univ, Med Coll, Shaoguan, Guangdong, Peoples R China

[3] Sun Yat sen Univ, Canc Ctr, Dept Colorectal Surg, 651 Dongfeng Rd East, Guangzhou 510060, Peoples R China

来源：

CANCER LETTERS | 2025年 / 631卷

关键词：

Colorectal cancer; Cancer associated fibroblasts; Oxaliplatin; Lactylation; ANTXR1; TUMOR; CELLS; CHEMORESISTANCE; PROGRESSION; EXPRESSION; MARKER; NICHE;

D O I：

10.1016/j.canlet.2025.217917

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Oxaliplatin is widely used in chemotherapy for patients with advanced colorectal cancer (CRC). However, frequent drug resistance limits its therapeutic efficacy in patients. Here, we found that a subset of cancer associated fibroblasts (CAFs) with activated glycolysis induced CRC resistance to oxaliplatin. Lactate derived from CAFs promoted the transcription of ANTXR1 through histone lactylation and induced ANTXR1 lactylation at lysine 453 residue. The increased expression of ANTXR1 and ANTXR1 K453la in CRC cells was correlated with oxaliplatin resistance in CRC cells and the poor prognosis of CRC patients. Mechanistically, lactylation promoted ANTXR1 stability and activated the RhoC/ROCK1/SMAD5 signal pathway, subsequently contributed to CRC stemness and oxaliplatin resistance. Genetic or pharmacologic inhibition of the lactate shuttle between CAFs and cancer cells improved chemotherapy efficiency in vitro and in cell/patient-derived xenograft models. These findings contribute to a better understanding of oxaliplatin resistance and indicates that inhibition of tumorstromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.

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页数：17

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