Patient-Derived Organoid Model in the Prediction of Chemotherapeutic Drug Response in Colorectal Cancer.

As an emerging technology in precision medicine, the patient-derived organoid (PDO) technology has been indicated to provide novel modalities to judge the sensitivity of individual tumors to cancer drugs. In this work, an in vitro model of colorectal cancer (CRC) was established using the PDO culture, and it is demonstrated that the PDO samples preserved, to a great extent, the histologic features and marker expression of the original tumor tissues. Subsequently, cancer drugs 5-FU, oxaliplatin, and irinotecan were selected and screened on five CRC PDO samples, while the patient-derived organoid xenograft (PDOX) model was applied for comparison. The receiver operating characteristic (ROC) curve was drawn according to the IC50 data from the PDO model and the relative tumor proliferation rate (T/C%) from PDOX. Interestingly, the area under the ROC curve was 0.84 (95% CI, 0.64-1.04, P value = 0.028), which suggested that the IC50 of cancer drugs from the PDO model was strongly correlated with PDOX responses. In addition, the optimal sensitivity cutoff value for drug screening in CRC PDOs was identified at 10.35 μM, which could act as a reference value for efficacy evaluation of 5-FU, oxaliplatin, and irinotecan in the colorectal cancer drug screening. Since there are no unified criteria to judge the sensitivity of drugs in vitro, our work provides a method for establishing in vitro evaluation criteria via PDO and PDOX model using the patient tissues received from local hospitals, exhibiting potential in clinical cancer therapy and precision medicine.

[1]  J. Tabernero,et al.  Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study , 2021, ESMO open.

[2]  T. Kondo,et al.  Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance. , 2021, Cancer letters.

[3]  John F. Ouyang,et al.  The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology , 2021, Nature Communications.

[4]  H. Nagano,et al.  Anti-cancer activity of amorphous curcumin preparation in patient-derived colorectal cancer organoids. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  Nancy T. Li,et al.  An Engineered Patient‐Derived Tumor Organoid Model That Can Be Disassembled to Study Cellular Responses in a Graded 3D Microenvironment , 2021, Advanced Functional Materials.

[6]  K. Chatterjee,et al.  3D Tumor Models for Breast Cancer: Whither We Are and What We Need. , 2021, ACS biomaterials science & engineering.

[7]  Y. Cho,et al.  Establishment of patient‐derived organotypic tumor spheroid models for tumor microenvironment modeling , 2021, Cancer medicine.

[8]  Ji Hun Yang,et al.  Drug screening by uniform patient derived colorectal cancer hydro-organoids. , 2021, Biomaterials.

[9]  D. Witonsky,et al.  Genomic and epigenomic active vitamin Dresponses in human colonic organoids. , 2021, Physiological genomics.

[10]  Shaohua Ma,et al.  Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids , 2021, Cancer biology & medicine.

[11]  E. Oki,et al.  Real-World Evidence on Second-Line Treatment of Metastatic Colorectal Cancer Using Fluoropyrimidine, Irinotecan, and Angiogenesis Inhibitor. , 2021, Clinical colorectal cancer.

[12]  Yoav Mayshar,et al.  Heterozygous APC germline mutations impart predisposition to colorectal cancer , 2021, Scientific Reports.

[13]  S. Batra,et al.  Recent advances in organoid development and applications in disease modeling. , 2021, Biochimica et biophysica acta. Reviews on cancer.

[14]  A. Hsieh,et al.  A bladder cancer patient-derived xenograft displays aggressive growth dynamics in vivo and in organoid culture , 2021, Scientific Reports.

[15]  Q. Cheng,et al.  A novel integrated system using patient-derived glioma cerebral organoids and xenografts for disease modeling and drug screening. , 2020, Cancer letters.

[16]  A. Atala,et al.  3-D Human Renal Tubular Organoids Generated from Urine-Derived Stem Cells for Nephrotoxicity Screening , 2020, ACS biomaterials science & engineering.

[17]  G. van der Pluijm,et al.  Patient-derived tumour models for personalized therapeutics in urological cancers , 2020, Nature Reviews Urology.

[18]  J. An,et al.  Lactobacillus-derived metabolites enhance the antitumor activity of 5-FU and inhibit metastatic behavior in 5-FU-resistant colorectal cancer cells by regulating claudin-1 expression , 2020, Journal of Microbiology.

[19]  Jun Yu,et al.  In Colorectal Cancer Cells With Mutant KRAS, SLC25A22-Mediated Glutaminolysis Reduces DNA Demethylation to Increase WNT Signaling, Stemness, and Drug Resistance. , 2020, Gastroenterology.

[20]  L. del Peso,et al.  Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue , 2020, Cancers.

[21]  M. Rubin,et al.  Patient-derived xenografts and organoids model therapy response in prostate cancer , 2020, Nature Communications.

[22]  Junjie Peng,et al.  Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer. , 2019, Cell stem cell.

[23]  L. Miller,et al.  Pleural Effusion Aspirate for use in 3D Lung Cancer Modeling and Chemotherapy Screening. , 2019, ACS biomaterials science & engineering.

[24]  A. Oudenaarden,et al.  Long‐term expanding human airway organoids for disease modeling , 2019, The EMBO journal.

[25]  F. Di Palma,et al.  Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy , 2019, Disease Models & Mechanisms.

[26]  Jijun Cheng,et al.  Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response , 2018, Cancer communications.

[27]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[28]  G. Risbridger,et al.  Preclinical Models of Prostate Cancer: Patient-Derived Xenografts, Organoids, and Other Explant Models. , 2018, Cold Spring Harbor perspectives in medicine.

[29]  Wei Chen,et al.  Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients , 2018, Cancer communications.

[30]  Andrea Sottoriva,et al.  Patient-derived organoids model treatment response of metastatic gastrointestinal cancers , 2018, Science.

[31]  Hans Clevers,et al.  A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity , 2018, Cell.

[32]  M. Reagan,et al.  3d Tissue Engineered In Vitro Models Of Cancer In Bone. , 2017, ACS biomaterials science & engineering.

[33]  B. Shi,et al.  Efficient growth suppression in pancreatic cancer PDX model by fully human anti-mesothelin CAR-T cells , 2017, Protein & Cell.

[34]  Rameen Beroukhim,et al.  Patient-derived xenografts undergo murine-specific tumor evolution , 2017, Nature Genetics.

[35]  B. Chabner,et al.  NCI-60 Cell Line Screening: A Radical Departure in its Time. , 2016, Journal of the National Cancer Institute.

[36]  Joshua M. Korn,et al.  High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response , 2015, Nature Medicine.

[37]  Bon-Kyoung Koo,et al.  Modeling mouse and human development using organoid cultures , 2015, Development.

[38]  J. Maris,et al.  Improving Patient Outcomes With Cancer Genomics: Unique Opportunities and Challenges in Pediatric Oncology. , 2015, JAMA.

[39]  Ash A. Alizadeh,et al.  Toward understanding and exploiting tumor heterogeneity , 2015, Nature Medicine.

[40]  Hayley E. Francies,et al.  Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients , 2015, Cell.

[41]  Liewei Wang,et al.  In vitro human cell line models to predict clinical response to anticancer drugs. , 2015, Pharmacogenomics.

[42]  M. Spector,et al.  Organoid Models of Human and Mouse Ductal Pancreatic Cancer , 2015, Cell.

[43]  Zachary C. Dobbin,et al.  Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer , 2014, Oncotarget.

[44]  Juergen A. Knoblich,et al.  Organogenesis in a dish: Modeling development and disease using organoid technologies , 2014, Science.

[45]  Jason R Spence,et al.  How to make an intestine , 2014, Development.

[46]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[47]  H. Clevers,et al.  Growing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications , 2013, Science.

[48]  Hans Clevers,et al.  Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. , 2011, Gastroenterology.

[49]  Hans Clevers,et al.  Isolation and in vitro expansion of human colonic stem cells , 2011, Nature Medicine.

[50]  K. Polyak,et al.  Tumor heterogeneity: causes and consequences. , 2010, Biochimica et biophysica acta.

[51]  H. Clevers,et al.  Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche , 2009, Nature.

[52]  C. Köhne,et al.  Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial , 2007 .

[53]  R. Shoemaker The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[54]  M. Komatsu,et al.  Predicting the chemosensitivity of ovarian and uterine cancers with the collagen gel droplet culture drug-sensitivity test , 2005, Anti-cancer drugs.

[55]  I. Fichtner,et al.  Anticancer drug response and expression of molecular markers in early-passage xenotransplanted colon carcinomas. , 2004, European journal of cancer.

[56]  E. Ruoslahti,et al.  Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. , 1998, Science.