Generation of induced pluripotent stem cell (iPSC) line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene

Griscelli, Frank; Oudrhiri, Noufϊssa; Féraud, Olivier; Divers, Dominique; Portier, Lucie; Turhan, Ali G.; Bennaceur-Griscelli, Annelise

doi:10.1016/j.scr.2017.09.003

Cited by 22 publications

(17 citation statements)

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“…Hereditary cancers are due to oncogenic mutations or deletions and represent a major challenge in terms of diagnosis, prognosis, and prevention [1]. Recently, the development of the iPSC technology allowed these cancers to be modeled using patient-derived pluripotent stem cells [2,3,4]. It has been shown that this strategy can be used for modeling BRCA1-mutated breast cancer [5] and Li–Fraumeni syndrome with TP53 deletions [3].…”

Section: Introductionmentioning

confidence: 99%

iPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

Hwang

Desterke

Féraud

et al. 2019

IJMS

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Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c-met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of “hereditary renal cancer in a dish” model using c-met-mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.

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Section: Introductionmentioning

confidence: 99%

iPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

Hwang

Desterke

Féraud

et al. 2019

IJMS

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“…The aim of our study was to evaluate the effect of BRCA1-deleted (BRCA1+/−) iMSCs on breast tumor development and progression, compared to iMSCs that contained two copies of BRCA1 (BRCA1+/+ iMSCs). The BRCA1+/− iMSCs used here were produced from iPSCs that were generated by reprogramming blood cells (PBMCs) from two patients with a heterozygous deletion of exon 17 of the BRCA1 gene [19].…”

Section: Discussionmentioning

confidence: 99%

“…Using PBMCs of these two affected family members and two normal (BRCA1 wildtype) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four Yamanaka reprogramming factors: OCT4, SOX2, KLF4, and c-MYC [18]. In previous publications, we characterized the iPSCs generated from P2 [19] and confirmed the deletion of exon 17 in BRCA1 by multiplex ligation-dependent probe amplification analysis [20]. All iPSC clones generated from Patient 1 demonstrated human embryonic stem cell morphology and expressed pluripotency factors (NANOG, SOX2 and OCT4) as well as stem cell-specific surface markers (TRA-1-60 and SSEA4) (Figure S1A,B).…”

Section: Generation and Characterization Of Ipscs And Derivation Of Induced Mesenchymal Stem Cells (Imscs)mentioning

confidence: 99%

“…All iPSC clones generated from Patient 1 demonstrated human embryonic stem cell morphology and expressed pluripotency factors (NANOG, SOX2 and OCT4) as well as stem cell-specific surface markers (TRA-1-60 and SSEA4) (Figure S1A,B). Importantly, the iPSC lines from both patients had normal karyotypes (Figure S1C) and demonstrated the capacity to differentiate into all three germ layers in vivo in teratomas (Figure S1D) [19].…”

Section: Generation and Characterization Of Ipscs And Derivation Of Induced Mesenchymal Stem Cells (Imscs)mentioning

confidence: 99%

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iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression

Portier

Desterke

Chaker

et al. 2021

IJMS

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Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/− who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+/− iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1α, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+/− iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+/− iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+/− iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer.

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“…Several iPSC lines have been established from patients with inherited cancer syndromes. These include those from patients harboring germline BRCA1 mutations predisposing to breast and ovarian cancers (Griscelli et al, 2017; Soyombo et al, 2013), from patients with neurofibromatosis type 1 (NF1) (Anastasaki et al, 2015; Wegscheid et al, 2018), and from those with Gorlin syndrome (Hasegawa et al, 2017). Directed differentiation strategies will enable researchers to use these lines to model development of the tissues that give rise to cancer in these syndromes.…”

Section: Considerations For Future Studies Using Stem Cells and Organmentioning

confidence: 99%

Constructing and Deconstructing Cancers using Human Pluripotent Stem Cells and Organoids

Smith

Tabar

2019

Cell Stem Cell

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Summary Cell lines and animal models have provided the foundation of cancer research for many years. However, human pluripotent stem cells (hPSCs) and organoids are increasingly enabling insights into tumor development, progression, and treatment. Here, we review recent studies using hPSCs to elucidate the reciprocal roles played by genetic alterations and cell identity in cancer formation. We also review studies using human organoids as models that recapitulate both intra- and inter-tumoral heterogeneity to gain new insights into tumorigenesis and treatment responses. Finally, we highlight potential opportunities for cancer research using hPSC-derived organoids and genome editing in the future.

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Generation of induced pluripotent stem cell (iPSC) line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene

Cited by 22 publications

References 5 publications

iPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

iPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression

Constructing and Deconstructing Cancers using Human Pluripotent Stem Cells and Organoids

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