Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity

Seclì, Laura; Avalle, Lidia; Poggio, Pietro; Fragale, Giuseppe; Cannata, Cristiana; Conti, Laura; Iannucci, Andrea; Carrà, Giovanna; Rubinetto, Cristina; Miniscalco, Barbara; Hirsch, Emilio; Poli, Valeria; Morotti, Alessandro; Andrea, Marco De; Turco, Emilia; Cavallo, Federica; Fusella, Federica; Brancaccio, Mara

doi:10.1158/0008-5472.can-20-3150

Cited by 20 publications

(29 citation statements)

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“…Indeed, high HMGB1 levels correlate with poor response to neoadjuvant chemotherapy in TNBC patients, 18 and HMGB1 protects BC cells from chemotherapy and promotes metastasis formation. 57 Moreover, other DAMPs that can activate TLR2 may be released into the TME following ICD-inducing chemotherapy, 6 , 7 , 43 and indeed we observed the release of HSP70, HSP90, HSP60, and HSC70 from doxorubicin-treated MDA-MB-231 cells. Other chaperones, such as Morgana, are known to be constitutively released from MDA-MB-231 cells and to signal through TLR2.…”

Section: Discussionsupporting

confidence: 54%

“…Most importantly, the addition of CU-CPT22 significantly improved doxorubicin apoptotic effect in WT-874, TUBO, 4T1, and MDA-MB-231 cells ( Figure 5j and Supplementary Fig 6b). Of note, treatment of MDA-MB-231 cells with doxorubicin, alone or combined with CU-CPT22, increased the release of HMGB1 and other DAMPs that can potentially bind TLR2, such as HSP70, HSP90, Morgana (CHORDC1), HSP60, and Heat shock cognate 71 kDa protein (HSC70) 43 (Supplementary Fig 7b), confirming the potential capability of doxorubicin to induce TLR2 activation on cancer cells. The effects of CU-CPT22 were not due to off-target mechanisms, as CU-CPT22 treatment did not exert any activity on KO-M26 or KO-E26 cells (Supplementary Fig 8a, b).…”

Section: Resultsmentioning

confidence: 60%

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Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy

et al. 2022

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Cancer stem cells (CSCs) are the main drivers of disease progression and chemotherapy resistance in breast cancer. Tumor progression and chemoresistance might then be prevented by CSC-targeted therapies. We previously demonstrated that Toll-like Receptor (TLR)2 is overexpressed in CSCs and fuels their self-renewal. Here, we show that high TLR2 expression is linked to poor prognosis in breast cancer patients, therefore representing a candidate target for breast cancer treatment. By using a novel mammary cancer-prone TLR2 KO mouse model, we demonstrate that TLR2 is required for CSC pool maintenance and for regulatory T cell induction. Accordingly, cancer-prone TLR2 KO mice display delayed tumor onset and increased survival. Transplantation of TLR2 WT and TLR2 KO cancer cells in either TLR2 WT or TLR2 KO hosts shows that tumor initiation is mostly sustained by TLR2 expression in cancer cells. TLR2 host deficiency partially impairs cancer cell growth, implying a pro-tumorigenic effect of TLR2 expression in immune cells. Finally, we demonstrate that doxorubicin-induced release of HMGB1 activates TLR2 signaling in cancer cells, leading to a chemotherapy-resistant phenotype. Unprecedented use of TLR2 inhibitors in vivo reduces tumor growth and potentiates doxorubicin efficacy with no negative impact on the host immune system, opening new perspectives for the treatment of breast cancer patients.

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 60%

Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy

et al. 2022

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“…Heat shock proteins (HSPs) are highly conserved polypeptides and essential for diverse cellular processes, such as recognition, signaling transduction, protein maturation, and cell differentiation ( Morimoto, 1998 ). In particular, many recent studies have indicated that HSP90α is strongly related to the proliferation and differentiation in cancer cells ( Secli et al, 2021 ; Zavareh et al, 2021 ; Zhang et al, 2021 ). To our knowledge, few reports regarding HSP90α in sepsis have been published.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the diagnostic and prognostic values of serum HSP90α in sepsis patients: a retrospective study

Zhang

Bocheng

et al. 2022

PeerJ

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Background Sepsis is a serious syndrome that is caused by immune responses dysfunction and leads to high mortality. The abilities of heat shock protein 90α (HSP90α) in assessing the diagnosis and prognosis in patients with sepsis remain ill-defined to date. We conducted a study to reveal the possible clinical applications of HSP90α as biomarker for the diagnosis and prognosis in patients with sepsis. Methods In total, 150 patients of sepsis, 110 patients without sepsis admitted to ICU and 110 healthy subjects were involved in this study. The serum HSP90α contents, sequential organ failure assessment (SOFA) scores, procalcitonin (PCT), and short-term survival status of the participants were measured and compared. Logistic and linear regression models adjusting for potential confounders were used to examine the association of HSP90α with sepsis survival. Moreover, serum IL-1β, IL-18, MIP-3α, and ENA-78 were also determined. Finally, Spearman correlation analysis was employed to reveal a possible mechanism that HSP90α contributed to the short-term deaths. Results Serum HSP90α levels in sepsis patients were higher than those in ICU controls and healthy controls (P < 0.001), and even increased in patients who died within 28 days (P < 0.001). Logistic and linear regression models identified HSP90α was an independent risk factors for sepsis mortality. Receiver operating characteristic (ROC) analysis displayed that HSP90α had a considerable predictive performance for sepsis outcome, with an area under curve (AUC) value up to 0.79. Survival analysis demonstrated that the mortality of sepsis individuals at 28 days was positively associated with HSP90α levels, especially the levels of HSP90α were greater than 120 ng/mL (P < 0.001). Moreover, among sepsis patients, those who died had notably elevated cytokines, IL-1β, IL-18, and chemokines, MIP-3α, ENA-78, relative to survivors. Further correlation analysis demonstrated that there was a nominally positive correlation between HSP90α and IL-1β, IL-18, and MIP-3α. Conclusion HSP90α is of favorable clinical significance in sepsis diagnosis and prognosis, laying a foundation for future clinical applications.

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“…The interaction between Morgana and TLR4 remains elusive and the possibility that TLR4 may participate to Morgana signal transduction thank to a cross-talk with TLR2 and LRP1 has to be taken into account. The fact that cancer cell migration in presence of Morgana blocking antibodies is not further repressed by inhibiting HSP90 suggests that the extracellular complex containing HSP90 and Morgana is the main responsible for migration, at least in a subgroup of cancer cells ( Seclì et al, 2021 ).…”

Section: Ehsp90 Complexes Activate Cancer Cell Surface Receptorsmentioning

confidence: 99%

“…mAb 5B11B3 systemic treatment in immunocompromised tumor-bearing mice inhibits cancer cell intravasation and metastasis. In syngeneic cancer mouse models, in addition to reducing metastases, mAb 5B11B3 abates tumor growth by promoting anti-cancer immunity mediated by macrophages and CD8 + T lymphocytes ( Seclì et al, 2021 ).…”

Section: Ehsp90 Complexes As Therapeutic Targetsmentioning

confidence: 99%

Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

Poggio

Sorge

Seclì

et al. 2021

Front. Cell Dev. Biol.

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HSP90 is released by cancer cells in the tumor microenvironment where it associates with different co-chaperones generating complexes with specific functions, ranging from folding and activation of extracellular clients to the stimulation of cell surface receptors. Emerging data indicate that these functions are essential for tumor growth and progression. The understanding of the exact composition of extracellular HSP90 complexes and the molecular mechanisms at the basis of their functions in the tumor microenvironment may represent the first step to design innovative diagnostic tools and new effective therapies. Here we review the impact of extracellular HSP90 complexes on cancer cell signaling and behavior.

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Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity

Cited by 20 publications

References 50 publications

Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy

Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy

Evaluation of the diagnostic and prognostic values of serum HSP90α in sepsis patients: a retrospective study

Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

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