A Biobank of Colorectal Cancer Patient-Derived Xenografts.
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ABSTRACT:
SUBMITTER: Abdirahman SM
PROVIDER: S-EPMC7563543 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
A Biobank of Colorectal Cancer Patient-Derived Xenografts.
Abdirahman Suad M SM Christie Michael M Preaudet Adele A Burstroem Marie C U MCU Mouradov Dmitri D Lee Belinda B Sieber Oliver M OM Putoczki Tracy L TL
Cancers 20200819 9
Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation of a biobank of CRC PDXs from stage I to stage IV patients. We demonstrate that PDXs within our biobank recapitulate the histopathological and mutation features of the origina ...[more]
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Project description:Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95% CI: 22.1%-50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435-42. ©2017 AACR.
| S-EPMC5562363 | biostudies-literature
Project description:Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~23% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing unique 25 patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. The study was designed to determine how stable patient-derived xenografts are across multiple transplant generations in mice, and to determine how closely xenografts established with pre-treatment samples cluster with xenografts established with post-treatment samples. Overall, pre-treatment and post-treatment samples derived from the same patient cluster together, and multiple transplant generations of xenografts derived from an individual patient cluster together.
| S-ECPF-GEOD-46106 | biostudies-other
Project description:PurposePatient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XL), derived from PDXs of colorectal cancer with matched patient germline gDNA available.Experimental designWhole-exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H, and MSI-like XLs using a reverse genetics functional approach.ResultsXLs recapitulated the entire spectrum of colorectal cancer transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion.ConclusionsThe XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.
| S-EPMC7611232 | biostudies-literature
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Project description:Tumor budding has been found to be of prognostic significance for several cancers, including colorectal cancer (CRC). Additionally, the molecular classification of CRC has led to the identification of different immune microenvironments linked to distinct prognosis and therapeutic response. However, the association between tumor budding and the different molecular subtypes of CRC and distinct immune profiles have not been fully elucidated. This study focused, firstly, on the validation of derived xenograft models (PDXs) for the evaluation of tumor budding and their human counterparts and, secondly, on the association between tumor budding and the immune tumor microenvironment by the analysis of gene expression signatures of immune checkpoints, Toll-like receptors (TLRs), and chemokine families. Clinical CRC samples with different grades of tumor budding and their corresponding PDXs were included in this study. Tumor budding grade was reliably reproduced in early passages of PDXs, and high-grade tumor budding was intimately related with a poor-prognosis CMS4 mesenchymal subtype. In addition, an upregulation of negative regulatory immune checkpoints (PDL1, TIM-3, NOX2, and IDO1), TLRs (TLR1, TLR3, TLR4, and TLR6), and chemokine receptors and ligands (CXCR2, CXCR4, CXCL1, CXCL2, CXCL6, and CXCL9) was detected in high-grade tumor budding in both human samples and their corresponding xenografts. Our data support a close link between high-grade tumor budding in CRC and a distinctive immune-suppressive microenvironment promoting tumor invasion, which may have a determinant role in the poor prognosis of the CMS4 mesenchymal subtype. In addition, our study demonstrates that PDX models may constitute a robust preclinical platform for the development of novel therapies directed against tumor budding in CRC.
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Project description:Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues (n = 11), PDX-tissues (n = 22), PDX-derived cell lines (n = 13), and patient-derived tumor cell lines (n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in murine cells, in PDX tissues and early thereof-derived cell cultures. We conclude that further analysis is needed concerning their impact on results obtained from studies performed with PDX but also with murine tumor models.
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