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

Abstract

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.

Design Artificial Stem Cell Nests for Stem Cell Niche in a Microfluidic Petri Dish Programmed by a Cell Phone

“…However, the ideal body-on-a-chip does not exist because the current microfluidic technology has many disadvantages. For example, the price of microfluidic chips and related equipment niche for leukemia; [29] mesenchymal stem cell niche for periodontal ligament remodeling; [30] vascular niche for tumor growth and metastasis; [31] hematopoietic stem cell niche for hematopoiesis; [32] adult neural stem cell niche for adult neurogenesis; [33] adult mammalian retinal stem cell niche for its activation in vivo; [34] bone marrow niches for hematological disease; [35] and stem cell niche factors for congenital enteropathy with ocular dysgenesis. [36] The niche brings intractable complexity.…”

“…[ 23 ] Stem cells accelerate tumor progression [ 24 ] while microenvironmental changes attract immune cells and stem cells. [ 25 ] There are studies about hematopoietic stem cell niche for transplantation or therapies; [ 26 ] cancer stem cell niche for cancer treatment; [ 27,28 ] bone marrow niche for leukemia; [ 29 ] mesenchymal stem cell niche for periodontal ligament remodeling; [ 30 ] vascular niche for tumor growth and metastasis; [ 31 ] hematopoietic stem cell niche for hematopoiesis; [ 32 ] adult neural stem cell niche for adult neurogenesis; [ 33 ] adult mammalian retinal stem cell niche for its activation in vivo; [ 34 ] bone marrow niches for hematological disease; [ 35 ] and stem cell niche factors for congenital enteropathy with ocular dysgenesis. [ 36 ] The niche brings intractable complexity.…”

Cancer Angiogenesis and Opportunity of Influence on Tumor by Changing Vascularization

“…Coinjection of these MSCs and 4T1 BC cells into the fatty pads of the mouse mammary gland caused highly aggressive tumor growth (a 2-fold increase in tumor volume compared to some cancer cells, p = 0.01283) and a higher spontaneous metastatic spread in the lungs [45].…”

DNA Damage Response and Cancer Metastasis: Clinical Implications and Therapeutic Opportunities

“…In xenograft models, cancer cells with silenced or altered DDR genes are allowed to form a primary tumor in the site of injection and then escape into lymphatic or blood circulation (spontaneous metastasis model) or are injected directly into mouse tail vein and allowed to circulate (experimental metastasis model) in immunocompromised mice. So far, data from xenograft models have reported both increased and decreased metastatic potentials related to different DDR gene defect (23,(29)(30)(31). In contrast, genetically engineered mouse models are more consistent in correlating DDR defects with increased metastatic potential (32)(33)(34)(35).…”