TY - JOUR
T1 - Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma
AU - Song, Shumei
AU - Xu, Yan
AU - Huo, Longfei
AU - Zhao, Shuangtao
AU - Wang, Ruiping
AU - Li, Yuan
AU - Scott, Ailing W.
AU - Pizzi, Melissa Pool
AU - Wang, Ying
AU - Fan, Yibo
AU - Harada, Kazuto
AU - Jin, Jiankang
AU - Ma, Lang
AU - Yao, Xiaodan
AU - Shanbhag, Namita D.
AU - Gan, Qiong
AU - Roy-Chowdhuri, Sinchita
AU - Badgwell, Brian D.
AU - Wang, Zhenning
AU - Wang, Linghua
AU - Ajani, Jaffer A.
N1 - Funding Information:
Conception and design: S. Song, J.A. Ajani; Development of methodology: Y Xu, LF Huo, S Zhao, R Wang, Y Li; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Y Xu, LF Huo, S Zhao, R Wang, Y Li, A.W. Scott, J. Jin, L Ma, M.P Pizzi, Y Wang, Y Fan, K Harada, X Yao, N Shanbhag, Q Gan, S Roy-Chowdhuri, B Badgwell, Z Wang, S Song, L Wang, JA Ajani. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Song, L Wang, LF Huo, S Zhao, R Wang, Y Xu, Y Li, J.A. Ajani, Z Wang; Writing, review, and/or revision of the manuscript: S Song, LF Huo, Y Xu, J.A. Ajani. Administrative, technical, or material support (i.e., reporting or organizing data, research materials, constructing databases): S. Song, ZN Wang, L Wang and J.A. Ajani. Study supervision: Song S. Other (financial support): J.A. Ajani; S Song. The authors read and approved the final manuscript.
Funding Information:
We appreciate Sarah Bronson, scientific editor in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for her excellent editing of English for this manuscript.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies. Methods: PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells. Results: We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo. Conclusion: We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.
AB - Background: Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies. Methods: PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells. Results: We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo. Conclusion: We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.
KW - Gastric adenocarcinoma
KW - Patient-derived cell lines
KW - Patient-derived orthotopic model
KW - Patient-derived xenograft, molecular profile
KW - Peritoneal metastases
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U2 - 10.1186/s13046-021-02003-8
DO - 10.1186/s13046-021-02003-8
M3 - Article
C2 - 34162421
AN - SCOPUS:85108791033
SN - 0392-9078
VL - 40
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
IS - 1
M1 - 207
ER -