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Open Access Elucidation of Breast Cancer Tissue Diversity by Comprehensive Analysis of Minimum Unit Omics

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In their research, the institute has demonstrated some of the basic mechanisms that stabilise cancer stemness. 'Since the HER2/3-PI3K-NFKB pathway involved in cell signalling is essential in cancer stemness, we examined downstream molecules in this pathway,' outlines Gotoh. 'We identified insulin-like growth factor 2 (IGF2) as a significant downstream molecule, because an anti-IGF2 antibody treatment prevented tumoursphere formations and tumour initiating activity in PDX models, which are characteristic of cancer stem-like cells. This occurred even when other growth factors or cytokines were present. IGF2-PI3K signalling was found to stimulate tumoursphere formation and enhance the expression of genes that favoured stemness.' Most significantly, they discovered a positive feedback circuit involving IGF2, allowing cancer stem cells to appear. To finally eradicate CSCs, it will be imperative to disrupt the circuit. For their research, Gotoh and colleagues have employed many useful and unique techniques. 'We are collecting breast cancer patient samples and culturing them as spheroids and organoids and constructing patient-derived xenograft models (PDXs),' Gotoh states. These xenograft models are important aspects of their study. Her team is implanting pieces of a patient tumours into a mouse that has been humanised—meaning their bodies have been colonised by human stem cells, and therefore human cancer can grow, to an extent, as it would in our bodies. Her researchers also utilise a variety of other methods, for example, omics analysis, which includes single-cell-transcriptome and exome sequencing, related to genetics, and metabolome analysis. 'This kind of investigation is vital to understanding the true composition of tumours, which are now known to be comprised of heterogeneous cell populations whose molecular mechanisms must be properly analysed to eventually achieve new therapies,' says Gotoh. Not only are their methods innovative, but the Division's collaborations in academia and industry have propelled their research to the next level, allowing for them to receive help from leaders in different fields to aid their endeavours. As an example, for single cell analysis and the single-cell-transcriptome analysis previously mentioned, the team needed several collaborators who were experts for culturing single cells and laboratory equipment specific for single cell analysis and single-cell-transcriptome analysis. They also have several collaborators in industry working with them to develop novel cancer therapies against the molecular targets they identified.
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Keywords: BREAST CANCER PATIENT; CANCER STEMNESS; EXOME SEQUENCING; INSULIN-LIKE GROWTH FACTOR 2 (IGF2); METABOLOME ANALYSIS; OMICS ANALYSIS; ORGANOIDS; PATIENT-DERIVED XENOGRAFT MODELS (PDXS); SINGLE-CELL-TRANSCRIPTOME; SPHEROIDS; TUMOUR INITIATING; TUMOURSPHERE FORMATIONS; XENOGRAFT MODELS

Document Type: Research Article

Publication date: March 1, 2019

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