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Patient-derived xenograft model identifies clinically relevant subtype-specific features of colorectal cancer

ABSTRACT: Colorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103340 | GEO | 2018/10/16

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

Project description:Background: In high-grade serous ovarian cancer (HGSOC) intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations, but frequent epigenetic alterations including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated. Aims of this study were to explore how representative HGSOC PDXs are for their corresponding patient tumors methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450K. Further, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the predictive/prognostic value of the identified genes. Results: Only 0.6-1.0% of all analyzed CpGs (388,696 CpGs) changed significantly (p<0.01) during propagation showing that HGSOC PDXs are epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6% of CpG sites in comparison to untreated PDXs (p<0.01, FDR<10%). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g. Src family kinase pathway). Particularly, C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p<0.05) with improved progression free survival and overall survival in HGSOC patients. Conclusion: HGSOC PDXs resemble the global epigenome of patients over many generations, which can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our results encourage future application of PDXs for cancer epigenome studies.

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Patient-derived xenograft model identifies clinically relevant subtype-specific features of colorectal cancer

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