Identification of two cancer stem cell-like populations in triple-negative breast cancer xenografts

Abstract

Gene expression analysis at the single-cell scale by next generation sequencing has revealed the existence of clonal dissemination in cancer metastasis. The current spatial analysis technologies elucidate the heterogeneity of cell-cell interactions in situ; however, further analysis is needed to elucidate the nature of tumor heterogeneity. To reveal the expressional heterogeneity and cell-cell interactions in primary tumors and metastases, we performed transcriptomic analysis of microtissues dissected from a triple-negative breast cancer (TNBC) cell line MDA-MB-231 xenograft model by our automated tissue microdissection punching technology. This multiple-microtissue transcriptome analysis revealed that there were existed three cell-type clusters in the primary tumor and axillary lymph node metastasis, two of which were cancer stem cell-like clusters (CD44/MYC-high, HMGA1-high). The CD44/MYC-high cluster showed aggressive proliferation with MYC expression. The HMGA1-high cluster exhibited HIF1A activation and upregulation of ribosomal processes. Furthermore, we developed a cell-cell Interaction (CCI) analysis to investigate the ligand-receptor interactions (cancer cell to stroma and stroma to cancer cell) in each spot. The CCI analysis revealed the interaction dynamics generated by the combination of cancer cells and stromal cells in primary tumors and metastases. Two cancer stem cell-like populations were also detected by the scRNA-seq analysis of TNBC patients. In addition, the gene signature of the HMGA1-high cancer stem cell-like cluster has the potential to serve as a novel biomarker for diagnosis. The mixture of these multiple cancer stem cell-like populations may cause differential anticancer drug resistance, increasing the difficulty of curing this cancer.

Association between HMGA1 and immunosuppression in hepatocellular carcinoma: A comprehensive bioinformatics analysis

“…[22,23] Silencing HMGA1 can block the metastasis of breast cancer and colorectal cancer and reduce the proportion of tumor stem cells. [24–26] As reported in a recent study, the high expression of HMGA1 may be induced by the secretion of breast cancer cells, and signals may be sent through the advanced glycation end-products receptor, which would promote invasiveness. [26] In addition, previous studies demonstrated that the overexpression of HMGA1 can regulate the epigenetic silencing of genes related to tumor progression.…”

Evaluation of mAb 2C5-modified dendrimer-based micelles for the co-delivery of siRNA and chemotherapeutic drug in xenograft mice model

“…Figures 10C and 10D display representative images of metastatic tumors in the liver. The MDA-MB-231 tumor used in the xenograft model is well-known to metastasize to various organs, including the liver, lymph nodes, lungs, bones, and brain [ 36 ]. Although the nanoparticle formulation inhibited cell migration in vitro , a similar effect was not observed in vivo at the current dose.…”

HOXB7induces STAT3-mediated transformation and lung metastasis in immortalized mammary gland NMuMG cells

“…A total of 1.0×10 6 NMuMG-luc-HOXB7 cells, NMuMG-luc-HOXB7-shGFP cells, or NMuMG-luc-HOXB7-shSTAT3#3 cells were transplanted into fourth fat pads of 6-weeks-old BALB/cSlc-nu/nu female mice as previously described (Nakayama et al . 2017; Nakayama et al . 2022).…”