Paracrine Secretion of IL8 by Breast Cancer Stem Cells Promotes Therapeutic Resistance and Metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA909589 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22560325.fastq.gz | Fastqsanger.gz | |||
| SRR22560326.fastq.gz | Fastqsanger.gz | |||
| SRR22560327.fastq.gz | Fastqsanger.gz | |||
| SRR22560328.fastq.gz | Fastqsanger.gz | |||
| SRR22560329.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population. Using a co-culture system in vitro and a co-implantation system in vivo, it is demonstrated herein that the breast cancer stem cell (BCSC) secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden. Hence, this study has delineated the mechanism by which BCSCs determine the therapeutic response and metastatic of bulk cancer cells; and thereby suggests novel therapeutic strategies to ameliorate breast cancer outcomes.
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Project description:BackgroundBreast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population.MethodsCo-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8.ResultsWe identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden.ConclusionTaken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes. Video Abstract.
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Project description:Breast cancers consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The mechanism and functional implications of the subpopulation equilibrium in cancer progression remain largely unknown. Herein, we report that BCSCs secretome conditioned bulk tumor cells developed resistance to anti-endocrine therapy both in vitro and in vivo. IL8 was significantly enriched in BCSCs secretome and blockade of IL8 signaling reversed the tamoxifen resistance induced by BCSCs. The enhanced Wnt/β-catenin signal simultaneously increased the secretion of IL8 in BCSCs, which leads to the seemingly contradictory behaviors of bulk tumor cells. Collectively, our study characterizes the paracrine effects and identifies key molecules secreted by BCSCs, which may become therapeutic vulnerabilities to overcome tamoxifen resistance.
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