2. Academic Validation
  3. Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer

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

  • Cancer Lett. 2025 Jul 17:631:217917. doi: 10.1016/j.canlet.2025.217917.
Jiahua He 1,  Weihao Li 1,  Song Wang 1,  Jin Lan 1,  Xuanlin Hong 2,  Leen Liao 1,  Da Kang 1,  Weifeng Wang 1,  Ruowei Wang 1,  Weili Zhang 1,  Long Yu 1,  Qingjian Ou 1,  Yujing Fang 1,  Xiaojun Wu 1,  Junzhong Lin 1,  Peirong Ding 3,  Chi Zhou 4,  Zhizhong Pan 5,  Jianhong Peng 6
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong, PR China.
  • 2 Medical College, Shaoguan University, Shaoguan, Guangdong, PR China.
  • 3 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong, PR China. Electronic address: dingpr@sysucc.org.cn.
  • 4 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong, PR China. Electronic address: zhouchi@sysucc.org.cn.
  • 5 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong, PR China. Electronic address: panzhzh@sysucc.org.cn.
  • 6 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong, PR China. Electronic address: pengjh@sysucc.org.cn.
PMID: 40683418 DOI: 10.1016/j.canlet.2025.217917
Abstract

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 tumor-stromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.

Keywords

ANTXR1; Cancer associated fibroblasts; Colorectal cancer; Lactylation; Oxaliplatin.

Figures
Products