Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer

Giessler, Klara M.; Kleinheinz, Kortine; Huebschmann, Daniel; Balasubramanian, Gnana Prakash; Dubash, Taronish D.; Dieter, Sebastian M.; Siegl, Christine; Herbst, Friederike; Weber, Sarah; Hoffmann, Christopher M.; Fronza, Raffaele; Buchhalter, Ivo; Paramasivam, Nagarajan; Eils, Roland; Schmidt, Manfred; Kalle, Christof von; Schneider, Martin; Ulrich, Alexis; Scholl, Claudia; Fröhling, Stefan; Weichert, Wilko; Brors, Benedikt; Schlesner, Matthias; Ball, Claudia R.; Glimm, Hanno

doi:10.1084/jem.20162017

Cited by 29 publications

(31 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrated that multiple distinct genomic subclones are present in the primary CRC tumor and PDX tumors. Moreover, our analysis indicated the dynamic expansion of minor subclones in PDX-MRA, which is consistent with previous genomic studies of PDX-bearing mice (20,21). These observations indicate that environmental selective pressures drive the development of minor pre-existing subclones in the initial establishment of PDX.…”

Section: Discussionsupporting

confidence: 91%

Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

Sato

Niida

Masuda

et al. 2018

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking. Materials and Methods: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses. Results: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA. Conclusion: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH. Cancer consists of multiple subclones with different genetic backgrounds (1). This intratumoral heterogeneity (ITH) is a major cause of the therapeutic difficulty because the presence of multiple subclones boosts adaptation to pharmacological 21 This article is freely accessible online.

show abstract

Section: Discussionsupporting

confidence: 91%

Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

Sato

Niida

Masuda

et al. 2018

Cancer Genomics Proteomics

View full text Add to dashboard Cite

show abstract

“…A leukemia study showed that 30% to 90% of subclones may disappear after each transplantation . By utilizing an integrative analytical approach that combines multiregional sequencing and genomic statistical and computational methods, researchers have shown that xenograft tumors present clonal dynamics through serial transplantation . Moreover, some subclones completely disappear during the serial transplantation of PDX models, and others become dominant (Fig.…”

Section: Intratumoral Heterogeneity (Ith)‐derived Mechanismmentioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

show abstract

“…Tumor-initiating cells can be enriched in serum-free 3D TSCs and upon xenotransplantation reliably form tumors in immunodeficient mice. These models faithfully reflect the original tumor histology and are functionally and genetically heterogeneous (23,24). Three TSCs with low, intermediate and high levels of CEA expression were tested for MV susceptibility ( Fig.…”

Section: Efficacy Of Mv-bite Against Patient-derived Colon Cancer Sphmentioning

confidence: 99%

Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors

Speck

Heidbuechel

Veinalde

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and tumor vaccination. To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested by complementary binding and cytotoxicity assays. efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers. We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells. MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. .

show abstract

Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer

Cited by 29 publications

References 49 publications

Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors

Contact Info

Product

Resources

About