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Reactivation of multipotency by oncogenic PIK3CA induces breast tumor heterogeneity

ABSTRACT: Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE69290 | GEO | 2015/08/13

SECONDARY ACCESSION(S): PRJNA285089

REPOSITORIES: GEO

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Project description:Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. Luminal and basal cells, or tumour cells, from mice in which expression of PIK3CA-H1047R and YFP (and in some conditions loss of p53) was targeted in basal cells using K5CREERT2 or in luminal cells using K8CREERT2 were FACS isolated and RNA was extracted before being hybridized Affymetrix microarrays.

Project description:Glandular epithelia including the mammary gland (MG) and the prostate are composed of basal cells (BC) and luminal cells (LC). Lineage tracing demonstrates that many glandular epithelia initially develop from multipotent basal stem cells (BaSCs) that are replaced in adult life by distinct pool of unipotent stem cells (SCs). However, adult unipotent BaSC can reactivate multipotency and give rise to LCs upon transplantation or oncogene expression, demonstrating the important plasticity of BaSCs in regenerative and pathological conditions, and suggesting that an active mechanism restricts multipotency in BaSCs during physiological conditions. The nature of this mechanism is currently unknown. Here, we assess whether basal and luminal cell-cell communication restricts multipotency in glandular epithelia. To this end, we performed lineage tracing of BCs together with the ablation of LCs in different adult glandular epithelia including MG, prostate, sweat glands and salivary glands and assessed the fate of BaSCs overtime. Interestingly, ablation of LCs reactivated multipotency in unipotent adult BaSCs from multiple epithelia. To understand the molecular mechanisms that controls multipotency in adult BaSCs, we performed population bulk-RNA-seq and single cell RNA-seq of FACS isolated adult mammary epithelial cells after LC ablation. Upon LC ablation, adult BCs activate a hybrid basal and luminal differentiation program before giving rise to LC, reminiscent of the genetic program that regulate multipotency during embryonic development. Different signaling pathways including Notch, Wnt and Egfr were activated in BaSC and their progeny following LC ablation and blocking these pathways inhibited adult BC multipotency. Altogether, our study demonstrates that heterotypic LC and BC communication is essential to maintain lineage fidelity in glandular epithelial SC during homeostasis and uncovers the lineage trajectory and signaling pathways that promote multipotency during tissue repair.

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Reactivation of multipotency by oncogenic PIK3CA induces breast tumor heterogeneity

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