Fishes harbor a huge resource of phenotypic diversity and are useful for understanding the genetic basis of morphological variation.However,it is difficult to transfer classical genetic mapping to most non-model speci...Fishes harbor a huge resource of phenotypic diversity and are useful for understanding the genetic basis of morphological variation.However,it is difficult to transfer classical genetic mapping to most non-model species.In this study,we performed a comparative sequence analysis of Fgfr1a to first interpret the evolution of this candidate scale-loss gene in 15 schizothoracine fishes with various scale phenotypes.While considerable amino acid(AA)substitutions were observed,molecular evolution analysis indicates that the overall coding regions were subject to functional constraint.We also identified extra copies of Fgfr1a in 4 scale-loss fishes and detected accelerated evolution in one AA substitution specific to these duplicates.We speculate that Fgfr1a had accumulated mutations in the ancestral lineage of scale-loss schizothoracine fishes before experiencing duplication events,which was further followed by the diversification of species.In silico mutation analysis predicted deleterious effects of the mutations while no disruptive molecular mechanism was detected.Collectively,our results highlight the important role of Fgfr1a gene in the adaptive evolution of schizothoracine fishes during their radiation in the Qinghai-Tibetan Plateau.展开更多
Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination str...Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.展开更多
基金supported by the grants from the Knowledge Innovation Project(KSCX2-EW-J-26)Youth Innovation Promotion Association Foundation of the Chinese Academy of Sciences.
文摘Fishes harbor a huge resource of phenotypic diversity and are useful for understanding the genetic basis of morphological variation.However,it is difficult to transfer classical genetic mapping to most non-model species.In this study,we performed a comparative sequence analysis of Fgfr1a to first interpret the evolution of this candidate scale-loss gene in 15 schizothoracine fishes with various scale phenotypes.While considerable amino acid(AA)substitutions were observed,molecular evolution analysis indicates that the overall coding regions were subject to functional constraint.We also identified extra copies of Fgfr1a in 4 scale-loss fishes and detected accelerated evolution in one AA substitution specific to these duplicates.We speculate that Fgfr1a had accumulated mutations in the ancestral lineage of scale-loss schizothoracine fishes before experiencing duplication events,which was further followed by the diversification of species.In silico mutation analysis predicted deleterious effects of the mutations while no disruptive molecular mechanism was detected.Collectively,our results highlight the important role of Fgfr1a gene in the adaptive evolution of schizothoracine fishes during their radiation in the Qinghai-Tibetan Plateau.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82172653 and 82472728)the Key Project of Developmental Biology and Breeding from Hunan Province(Grant No.2022XKQ0205)+1 种基金the Research Team for Reproduction Health and Translational Medicine of Hunan Normal University(Grant No.2023JC101)the Natural Science Foundation of Hunan Province(Grant No.2025JJ80150).
文摘Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.
