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Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models.

ABSTRACT: Genetic heterogeneity within a tumor arises by clonal evolution, and patients with highly heterogeneous tumors are more likely to be resistant to therapy and have reduced survival. Clonal evolution also occurs when a subset of cells leave the primary tumor to form metastases, which leads to reduced genetic heterogeneity at the metastatic site. Although this process has been observed in human cancer, experimental models which recapitulate this process are lacking. Patient-derived tumor xenografts (PDX) have been shown to recapitulate the patient's original tumor's intra-tumor genetic heterogeneity, as well as its genomics and response to treatment, but whether they can be used to model clonal evolution in the metastatic process is currently unknown. Here, we address this question by following genetic changes in two breast cancer PDX models during metastasis. First, we discovered that mouse stroma can be a confounding factor in assessing intra-tumor heterogeneity by whole exome sequencing, thus we developed a new bioinformatic approach to correct for this. Finally, in a spontaneous, but not experimental (tail-vein) metastasis model we observed a loss of heterogeneity in PDX metastases compared to their orthotopic "primary" tumors, confirming that PDX models can faithfully mimic the clonal evolution process undergone in human patients during metastatic spreading.

SUBMITTER: Sprouffske K

PROVIDER: S-EPMC7026725 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models.

Sprouffske Kathleen K Kerr Grainne G Li Cheng C Prahallad Anirudh A Rebmann Ramona R Waehle Verena V Naumann Ulrike U Bitter Hans H Jensen Michael R MR Hofmann Francesco F Brachmann Saskia M SM Ferretti Stéphane S Kauffmann Audrey A

Computational and structural biotechnology journal 20200131

Genetic heterogeneity within a tumor arises by clonal evolution, and patients with highly heterogeneous tumors are more likely to be resistant to therapy and have reduced survival. Clonal evolution also occurs when a subset of cells leave the primary tumor to form metastases, which leads to reduced genetic heterogeneity at the metastatic site. Although this process has been observed in human cancer, experimental models which recapitulate this process are lacking. Patient-derived tumor xenografts ...[more]

PMID: 32099592

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Project description:BackgroundEndometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.MethodsHere, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.ResultsPDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.ConclusionsEC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Project description:ObjectivePatient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.MethodsA total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.ResultsA large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics.ConclusionsOur established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

Dataset Information

Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models.

Publications

Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models.

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