Browsing by Author "Rogers, Amber"

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    Correction: Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer
    (Springer Nature, 2024-06-22) Atwani, Rula; Nagare, Rohit Pravin; Rogers, Amber; Prasad, Mayuri; Lazar, Virginie; Sandusky, George; Tong, Yan; Pin, Fabrizio; Condello, Salvatore; Obstetrics and Gynecology, School of Medicine
    Correction: J Exp Clin Cancer Res 43, 156 (2024) 10.1186/s13046-024-03083-y Following publication of the original article [1], the authors identified an error in the author name of Rohit Pravin Nagare. The incorrect author name is: Rohit Nagare The correct author name is: Rohit Pravin Nagare The author group has been updated above and the original article [1] has been corrected.
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    Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer
    (Springer Nature, 2024-06-01) Atwani, Rula; Nagare, Rohit Pravin; Rogers, Amber; Prasad, Mayuri; Lazar, Virginie; Sandusky, George; Tong, Yan; Pin, Fabrizio; Condello, Salvatore; Obstetrics and Gynecology, School of Medicine
    Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.
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    Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer
    (Research Square, 2024-03-13) Atwani, Rula; Rogers, Amber; Nagare, Rohit; Prasad, Mayuri; Lazar, Virginie; Sandusky, George; Pin, Fabrizio; Condello, Salvatore; Obstetrics and Gynecology, School of Medicine
    Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
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    Sex hormone deficiency in male and female mice expressing the Alzheimer’s disease-associated risk-factor TREM2 R47H variant impacts the musculoskeletal system in a sex- and genotype-dependent manner
    (Oxford University Press, 2024-11-13) Pianeta, Roquelina; Deosthale, Padmini; Sanz, Natasha; Kohler, Rachel; Okpara, Chiebuka; Arnett, Matthew; Asad, Iqra; Rogers, Amber; Gerbig, Madison; Essex, Alyson; Liu, Ziyue; Wallace, Joseph M.; Plotkin, Lilian I.; Anatomy, Cell Biology and Physiology, School of Medicine
    The R47H variant of the triggering receptor expressed on myeloid cells 2 (TREM2) is a risk factor for Alzheimer's disease in humans and leads to lower bone mass accrual in female but not male 12-mo-old mice. To determine whether, as with aging, gonadectomy results in sex-specific musculoskeletal effects, gonad removal or SHAM surgery was performed in 4-mo-old TREM2R47H/+ mice and WT male and female littermates (n = 10-12/group), with sexes analyzed separately. Body weight was lower in males, but higher in females after gonadectomy, independently of their genotype. Gonadectomy also leads to decreased BMD in males at all sites and in the whole body (total) and spine in female mice for both genotypes. Total and femur BMD was lower in gonadectomized male mice 6-wk post-surgery, independently of the genotype. On the other hand, BMD was only lower in ovariectomized WT but not TREM2R47H/+ mice in all sites measured at this time point. Bone formation and resorption marker levels were not affected by orchiectomy, whereas CTX was higher 3 wk after surgery and P1NP showed a tendency toward lower values at the 6-wk time point only in ovariectomized WT mice. Micro-CT analyses showed no differences resulting from gonadectomy in structural parameters in femoral cortical bone for either sex, but lower tissue mineral density in males of either genotype 6-wk post-surgery. Nevertheless, biomechanical properties were overall lower in gonadectomized males of either genotype, and only for WT ovariectomized mice. Distal femur cancellous bone structure was also affected by gonadectomy in a genotype- and sex-dependent manner, with genotype-independent changes in males, and only in WT female mice. Thus, expression of the TREM2 R47H variant minimally alters the impact of gonadectomy in the musculoskeletal system in males, whereas it partially ameliorates the consequences of ovariectomy in female mice.