Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer

Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K.; Perna, Fabiana; Bowman, Robert L.; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie; Feldman, Michael D.; Mao, Jun J.; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H.; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafè, Massimiliano; Bromberg, Jacqueline

doi:10.1038/ncomms10442

Cited by 155 publications

(159 citation statements)

References 26 publications

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“…Interestingly, we show that IL-6, one of the known targets genes of NF-κB, is potently downregulated by the inhibitors. IL-6 has been recently linked to cancer stemness in multiple cancer models (Sansone et al, 2016; van der Zee et al, 2015). The exact mechanism by which NF-κB is inactivated by desaturase inhibitors in CSCs remains undefined.…”

Section: Discussionmentioning

confidence: 99%

Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells

et al. 2017

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SUMMARY Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral stimulated Raman scattering imaging of single living cells and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells. Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that NF-κB directly regulates the expression levels of lipid desaturases and that inhibition of desaturases blocks NF-κB signaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker for ovarian CSCs and a target for CSC-specific therapy.

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Section: Discussionmentioning

confidence: 99%

Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells

et al. 2017

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“…A recent preclinical study by Sansone et al (2016) found that chronic hormone therapy of mice with ER-positive luminal breast cancer led to induction of a dormant, CD133 high /ER low /mitochondria low population of cells, which produced IL-6 in an autocrine manner. These cells showed an increase in pluripotency genes and were able to exit dormancy by utilizing IL-6/Stat3/Notch3-driven, ER-independent self-renewal and mitochondria reactivation.…”

Section: Reactivation From Dormancymentioning

confidence: 99%

“…These cells showed an increase in pluripotency genes and were able to exit dormancy by utilizing IL-6/Stat3/Notch3-driven, ER-independent self-renewal and mitochondria reactivation. The use of an anti-IL6R antibody restored ER expression in HT-resistant cells and double treatment with HT/anti-IL6R antibodies in vivo was effective even in HT-resistant tumors (Sansone et al, 2016). These results demonstrate that dormancy may be induced by therapy and that microenvironment-derived cytokines such as IL-6 may be able to reawaken dormant cells.…”

Section: Reactivation From Dormancymentioning

confidence: 99%

The Relationship Between Dormant Cancer Cells and Their Microenvironment

Linde

Fluegen

Aguirre‐Ghiso

2016

Advances in Cancer Research

133

131

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The majority of cancer deaths are due to metastases that can occur years or decades after primary tumor diagnosis and treatment. Disseminated tumor cells (DTCs) surviving in a dormant state in target organs appear to explain the timing of this phenomenon. Knowledge on this process is important as it might provide a window of opportunity to prevent recurrences by eradicating dormant DTCs and/or by maintaining DTCs in a dormant state. Importantly, this research might offer markers of dormancy for early monitoring of metastatic relapse. However, our understanding of the mechanisms underlying the regulation of entry into and exit from dormancy is still limited and crippling any therapeutic opportunity. While cancer cell-intrinsic signaling pathways have been linked to dormancy regulation, it is likely that these pathways and the switch controlling reactivation from dormancy are regulated by microenvironmental cues. Here we review and discuss recent findings on how the microenvironment regulates cancer dormancy and raise new questions that may help advance the field.

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“…The acquisition of resistance manifests with a partial epithelial-mesenchymal transition (EMT) and increased migratory and invasive activity both in anti-estrogen-resistant cell line models (14) and in clinical samples (14)(15)(16)(17). Furthermore, a subset of tumor-initiating cells with stem-like characteristics (cancer stem cells: CSCs) is enriched in tamoxifen-resistant breast cancers and may demonstrate resistance to endocrine therapies, thus contributing to disease recurrence and metastatic progression (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Piggott

Silva

Robinson

et al. 2018

Clinical Cancer Research

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Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrineresistant and endocrine-na€ ve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrineresistant, compared with 8% endocrine-na€ ve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential.

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Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer

Cited by 155 publications

References 26 publications

Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells

Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells

The Relationship Between Dormant Cancer Cells and Their Microenvironment

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

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