Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037019302879 |
| _version_ | 1818325406107828224 |
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| author | Kathleen Sprouffske Grainne Kerr Cheng Li Anirudh Prahallad Ramona Rebmann Verena Waehle Ulrike Naumann Hans Bitter Michael R Jensen Francesco Hofmann Saskia M Brachmann Stéphane Ferretti Audrey Kauffmann |
| author_facet | Kathleen Sprouffske Grainne Kerr Cheng Li Anirudh Prahallad Ramona Rebmann Verena Waehle Ulrike Naumann Hans Bitter Michael R Jensen Francesco Hofmann Saskia M Brachmann Stéphane Ferretti Audrey Kauffmann |
| author_sort | Kathleen Sprouffske |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T11:43:58Z |
| format | Article |
| id | doaj.art-f59eeb0474a14975baefb2770967be51 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-13T11:43:58Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-f59eeb0474a14975baefb2770967be512022-12-21T23:47:34ZengElsevierComputational and Structural Biotechnology Journal2001-03702020-01-0118323331Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft modelsKathleen Sprouffske0Grainne Kerr1Cheng Li2Anirudh Prahallad3Ramona Rebmann4Verena Waehle5Ulrike Naumann6Hans Bitter7Michael R Jensen8Francesco Hofmann9Saskia M Brachmann10Stéphane Ferretti11Audrey Kauffmann12Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland; Corresponding authors.Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandBiotherapeutic and Analytical Technologies, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USADisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, SwitzerlandDisease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2001037019302879HeterogeneityClonal evolutionBreast cancerMetastasisPatient derived xenograft models |
| spellingShingle | Kathleen Sprouffske Grainne Kerr Cheng Li Anirudh Prahallad Ramona Rebmann Verena Waehle Ulrike Naumann Hans Bitter Michael R Jensen Francesco Hofmann Saskia M Brachmann Stéphane Ferretti Audrey Kauffmann Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models Computational and Structural Biotechnology Journal Heterogeneity Clonal evolution Breast cancer Metastasis Patient derived xenograft models |
| title | Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models |
| title_full | Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models |
| title_fullStr | Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models |
| title_full_unstemmed | Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models |
| title_short | Genetic heterogeneity and clonal evolution during metastasis in breast cancer patient-derived tumor xenograft models |
| title_sort | genetic heterogeneity and clonal evolution during metastasis in breast cancer patient derived tumor xenograft models |
| topic | Heterogeneity Clonal evolution Breast cancer Metastasis Patient derived xenograft models |
| url | http://www.sciencedirect.com/science/article/pii/S2001037019302879 |
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