Identification Of Oxaliplatin-chemoresistance Targets For Colorectal Cancer And The Construction Bioengineering Exosomes For Targeted Cancer Therapy

Colorectal cancer(CRC)is one of the most common malignancies.The incidence and mortality of CRC rank third among cancers.Early-stage CRC Patients with early-stage CRC can be treated more optimally with radical surgery.However,the treatment of patients with progressive CRC is based on a combination of surgical treatment and chemotherapy,and patients’ resistance to chemotherapeutic drugs greatly limits the effectiveness of treatment,resulting in poor quality of life and low survival rates,thus causing no significant improvement in the overall survival of CRC patients.Therefore,chemoresistance in CRC patients is an important cause of poor outcomes and poor prognosis.Chemotherapy resistance to multiple drugs in CRC is an important cause of treatment failure.Oxaliplatin(OXA),the third generation of platinum-based antitumor agents,is currently recommended by guidelines for the treatment of patients with progressive CRC and has shown significant clinical efficacy.Unfortunately,the molecular mechanism of chemoresistance in CRC has not been revealed.There are still a significant number of CRC patients with primary drug resistance,which greatly limits the effectiveness of treatment and leads to low quality of life and survival rate.Therefore,it is important to elucidate the molecular biological mechanism of chemoresistance and discover new targets for reversing chemoresistance for CRC clinical treatment.In summary,this study mainly includes the following points:(1)We identified Matrix GLA Protein(MGP)encoding gene(MGP)as a key regulator in CRC OXA chemoresistance via bioinformatics analysis,clinical specimens validation and in vitro and in vivo studies.We hypothesized that the MGP regulates chemoresistance via upregulating ATPase copper transporting alpha(ATP7A),ATPase copper transporting beta(ATP7A)and downregulating Copper Transporter 1(CTR1).(2)Next,we screened chemoresistance therapeutic targets for CRC patients via including larger clinical cohorts and high-throughput sequencing.Then,Coil-coil Domain-Containing Protein 80 encoding gene(CCDC80)were identified as a regulator for OXA chemoresistance and distant metastasis.We found that the CCDC80 may regulated tumor liver metastasis via epithelial mesenchymal transition(EMT)signaling pathway and promoting tumor chemoresistance by regulating ATP-binding cassette family(ABCA)members.(3)Finally,based on the finding of the novel chemoresistance targets for CRC patients,we developed tumor gene therapy base on the primary tumor-derived cell-derived engineered exosomes.We extracted primary cells from CRC patients,isolating and purifying the tumor cell derived exosomes.We found out the primary cell-derived exosomes were tended to accumulating to the tumor site,which implied the exosomes has the homing ability.Next,we constructing the bioengineered exosomes that carrying the therapeutic si RNAs.The bioengineered exosomes exhibited ideal anti-tumor ability in the mice model of liver metastasis,patient derived xenograft(PDX),patient derived organoids(PDO),and patient derived organoids xenograft(PDOX).