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Breast tumours maintain a reservoir of subclonal diversity during expansion.

ABSTRACT: Our knowledge of copy number evolution during the expansion of primary breast tumours is limited^1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

SUBMITTER: Minussi DC

PROVIDER: S-EPMC8049101 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Breast tumours maintain a reservoir of subclonal diversity during expansion.

Minussi Darlan C DC Nicholson Michael D MD Ye Hanghui H Davis Alexander A Wang Kaile K Baker Toby T Tarabichi Maxime M Sei Emi E Du Haowei H Rabbani Mashiat M Peng Cheng C Hu Min M Bai Shanshan S Lin Yu-Wei YW Schalck Aislyn A Multani Asha A Ma Jin J McDonald Thomas O TO Casasent Anna A Barrera Angelica A Chen Hui H Lim Bora B Arun Banu B Meric-Bernstam Funda F Van Loo Peter P Michor Franziska F Navin Nicholas E NE

Nature 20210324 7853

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited<sup>1,2</sup>. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary ana ...[more]

PMID: 33762732

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Project description:PurposeGlioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities.Experimental designWe developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs.ResultsThese studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors.ConclusionsThese findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.

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Breast tumours maintain a reservoir of subclonal diversity during expansion.

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Breast tumours maintain a reservoir of subclonal diversity during expansion.

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