Lymph node metastasis is crucial for esophageal squamous cell carcinoma(ESCC)malignancy.However,the molecular drivers and related mechanisms of lymph node metastasis in ESCC cells are unclear.In the present study,we f...Lymph node metastasis is crucial for esophageal squamous cell carcinoma(ESCC)malignancy.However,the molecular drivers and related mechanisms of lymph node metastasis in ESCC cells are unclear.In the present study,we found that the tyrosine kinase complex-focal adhesion kinase(FAK)/Src family kinase(SFK)axis specifically contributes to metabolic reprogramming by inducing the phosphorylation of ATP-citrate synthase(ACLY)Tyr542,Tyr652,and fructose-bisphosphate aldolase A(ALDOA)Tyr174,Tyr302,or Tyr328 sites in both primary and metastatic ESCC cells.Mechanistically,activated ACLY and ALDOA and their metabolites drive a transcriptional program in primary tumors that induces cyclin-dependent kinase 7/9(CDK7/9)complex-mediated expression of DNA replication-and cell proliferation-related molecules.This process functions as an enabler of tumor malignancy.In metastatic tumor cells,metabolic enzymes and their products facilitate the transcriptional activity of Yamanaka factors to induce the activation of downstream plasticity-related molecules,fueling ESCC cell survival within metastatic lymph nodes.FAK/SFK axis-controlled ACLY and ALDOA tyrosine phosphorylation and downstream transcription factors and effectors in primary and metastatic ESCC cells are strongly associated with poor patient outcomes.We discovered a lead compound,quercetagitrin,that inhibits the phosphorylation of ALDOA at Tyr174,302,and 328.Moreover,it has been shown to have antitumor effects alone or in combination with FAK/SFK inhibitors both in vivo and in vitro.The inhibition of tyrosine kinase-regulated metabolic enzyme activities and related signaling networks may be a potential strategy for the treatment and diagnosis of metastatic ESCC.展开更多
基金supported by the National Natural Science Foundation of China(82588201,81830086,and 81972243)Suzhou Top-Notch Talent Groups(ZXD2022003)+2 种基金the Major Program of Shenzhen Bay Laboratory(S201101004)the Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of the San-ming Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Lymph node metastasis is crucial for esophageal squamous cell carcinoma(ESCC)malignancy.However,the molecular drivers and related mechanisms of lymph node metastasis in ESCC cells are unclear.In the present study,we found that the tyrosine kinase complex-focal adhesion kinase(FAK)/Src family kinase(SFK)axis specifically contributes to metabolic reprogramming by inducing the phosphorylation of ATP-citrate synthase(ACLY)Tyr542,Tyr652,and fructose-bisphosphate aldolase A(ALDOA)Tyr174,Tyr302,or Tyr328 sites in both primary and metastatic ESCC cells.Mechanistically,activated ACLY and ALDOA and their metabolites drive a transcriptional program in primary tumors that induces cyclin-dependent kinase 7/9(CDK7/9)complex-mediated expression of DNA replication-and cell proliferation-related molecules.This process functions as an enabler of tumor malignancy.In metastatic tumor cells,metabolic enzymes and their products facilitate the transcriptional activity of Yamanaka factors to induce the activation of downstream plasticity-related molecules,fueling ESCC cell survival within metastatic lymph nodes.FAK/SFK axis-controlled ACLY and ALDOA tyrosine phosphorylation and downstream transcription factors and effectors in primary and metastatic ESCC cells are strongly associated with poor patient outcomes.We discovered a lead compound,quercetagitrin,that inhibits the phosphorylation of ALDOA at Tyr174,302,and 328.Moreover,it has been shown to have antitumor effects alone or in combination with FAK/SFK inhibitors both in vivo and in vitro.The inhibition of tyrosine kinase-regulated metabolic enzyme activities and related signaling networks may be a potential strategy for the treatment and diagnosis of metastatic ESCC.
