A5049564276- Protein Degradation and Inhibitors
- Melanoma and MAPK Pathways
- Click Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Cell Adhesion Molecules Research
- Renal cell carcinoma treatment
- RNA regulation and disease
- Renal and related cancers
- Cancer Genomics and Diagnostics
- Brain Metastases and Treatment
- Advanced biosensing and bioanalysis techniques
- Nanoplatforms for cancer theranostics
- PI3K/AKT/mTOR signaling in cancer
- CRISPR and Genetic Engineering
- Ferroptosis and cancer prognosis
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- RNA modifications and cancer
- Biotin and Related Studies
- Cellular Mechanics and Interactions
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- TGF-β signaling in diseases
- Histone Deacetylase Inhibitors Research
- Telomeres, Telomerase, and Senescence
Huntsman Cancer Institute
2017-2025
University of Utah
2015-2025
Abstract There is a critical need to improve our understanding of the pathogenesis melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor IHC. demonstrated heterogeneity immune infiltrates that correlated prior radiation post-craniotomy survival. Comparison identified significant immunosuppression enrichment oxidative...
Metastases are the major cause of melanoma-related mortality. Previous studies implicating aberrant AKT signaling in human melanoma metastases led us to evaluate effect activated AKT1 expression non-metastatic BRAF(V600E)/Cdkn2a(Null) mouse melanomas vivo. Expression resulted highly metastatic with lung and brain 67% 17% our mice, respectively. Silencing PTEN cooperated AKT1, resulting decreased tumor latency development nearly 80% tumor-bearing mice. These data demonstrate that activation...
Abstract Alterations in the PI3K/AKT pathway occur up to 70% of melanomas and are associated with disease progression. The three AKT paralogs highly conserved but data suggest they have distinct functions. Activating mutations AKT1 AKT3 human melanoma their role formation metastasis remains unclear. Using an established mouse model, we evaluated E17K, E40K, Q79K AKT1, AKT2, show that mice harboring tumors expressing AKT1E17K had highest incidence brain lowest mean survival. Tumors displayed...
Melanoma mortality is driven by the formation and growth of distant metastases. Here, we interrogated role tumor oxidative phosphorylation (OXPHOS) in metastases melanoma. OXPHOS was most upregulated metabolic pathway primary tumors that formed RCAS-TVA mouse model spontaneous lung brain metastases, melanoma patients developed or other Knockout PGC1α melanocytes had no impact on formation, but markedly reduced incidence Genetic knockout a component electron transport chain complex I, NDUFS4,...
This study addresses the urgent need for effective therapies patients with brain metastases from cutaneous melanoma, a major cause of treatment failure despite recent therapeutic advances. Utilizing mouse models that mimic human melanoma metastases, this investigates necessity focal adhesion kinase (FAK) in development distant and its potential as target. Pharmacological inhibition FAK demonstrates significant efficacy reducing preclinical models. Importantly, provides insight into crosstalk...
Abstract Melanoma has an unusual capacity to spread in early-stage disease, prompting aggressive clinical intervention very thin primary tumors. Despite these proactive efforts, patients with low-risk, low-stage disease can still develop metastasis, indicating the presence of permissive cues for distant spread. Here, we show that constitutive activation small GTPase ARF6 (ARF6Q67L) is sufficient accelerate metastasis mice BRAFV600E/Cdkn2aNULL melanoma at a similar incidence and severity Pten...
The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600E mutations. Although the initial response these inhibitors can be dramatic, sometimes causing complete tumor regression, majority melanomas eventually become resistant. Mitogen-activated protein kinase (MEK) mutations are found in primary frequently reported BRAF that develop resistance therapy; however, is a molecularly heterogeneous cancer, which...
Dysregulated protein kinase B alpha (PKB/AKT1) signaling has been increasingly implicated in melanoma metastasis to distant organs, especially the brain. In a recent study, we expressed activated AKT1 non-metastatic model vivo and discovered that activation decreased tumor latency elicited lung brain metastases this context.
Abstract Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 3 (AKT1–3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition AKT1–3 melanoma cells. Although pharmacological was without effect, silencing all three paralogs significantly...
Targeted therapies have revolutionized cancer care, but the development of resistance remains a challenge in clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected resistant tumors following genetic suppression NRAS expression. Complete tumor regression was observed all mice, 40% recurred. Analysis showed that most common mechanism overexpression activation receptor tyrosine kinases (RTKs). Interestingly, commonly...
Abstract Despite promising results from recent FDA-approved therapies, many advanced melanoma patients develop resistance to both immunotherapy and targeted therapy. A common mechanism therapy is upregulation of the PI3K/AKT signaling pathway, which has also been shown promote development brain metastases. Historically, AKT inhibitors have failed in clinic due their limited efficacy or intolerable toxicity. Proteomic analysis comparing non-metastatic vs metastatic primary tumors mice...
Abstract Adult granulosa cell tumor (AGCT) is a subtype of sex-cord stromal tumors and accounts for ~5% all ovarian neoplasms. Nearly 100% AGCT cases are caused by an oncogenic point mutation in the Forkhead Box L2 (FOXL2) transcription factor. Weis-Banke et al. found this gain-of-function (FOXL2C134W) allows FOXL2 to hijack nuclear SMAD2/3/4 complex, downstream effector transforming growth factor- ß (TGF-ß), redirect novel sites, inducing epithelial mesenchymal transition (EMT) other...
<p>Supplementary Figure S2 shows the classification of MTG001 and MTG004. Immunoblotting MTG004 PDX-derived cell lines showed similar levels P-AKT (Ser473), total AKT, P-ERK (Thr202/Tyr204), ERK1/2, P-Ribosomal S6 Kinase (Ser235/236), Kinase. GAPDH was used as a loading control. The cells exhibited higher PTEN. Analysis RNA sequencing data demonstrated that both express wildtype PTEN.</p>
<p>Supplementary Figure S1 shows that pharmacological inhibition of AKT has little effect on melanoma cells. Cell confluency assay under inhibition. A375, HT144, SK-MEL28, WM793, MTG001, and MTG004 cells were largely resistant to inhibitors MK2206 (2.5 µM) GDC0068 (1µM) while SK-MEL 28 MTG001 sensitive PI3Kα by GDC0941 (P < 0.001). Error bars indicate standard error the mean triplicate wells.</p>
<p>Supplementary Figure S2 shows the classification of MTG001 and MTG004. Immunoblotting MTG004 PDX-derived cell lines showed similar levels P-AKT (Ser473), total AKT, P-ERK (Thr202/Tyr204), ERK1/2, P-Ribosomal S6 Kinase (Ser235/236), Kinase. GAPDH was used as a loading control. The cells exhibited higher PTEN. Analysis RNA sequencing data demonstrated that both express wildtype PTEN.</p>
<p>Supplementary Figure S4 demonstrates that siAKT1-3 is specific for human AKT. A, The cell confluency assay of YUMM1.1 mouse melanoma cells under genetic inhibition demonstrated no effect on death with siAKT1, siAKT2, siAKT3, or any combination. Error bars indicate standard error the mean triplicate wells. B, Immunoblotting treated siCtrl vs siAKT1-3. No knockdown P-AKT (Ser473) P-PRAS40 (T246) indicated specificity siRNAs AKT.</p>
<p>Supplementary Figure S7 shows chemical structures of all pharmacological agents utilized in study, including MK2206, GSK2141795, GDC-0941, BYL719, RapaLink-1, GSK650394, GDC-0068, GDC-0084, and INY-03-041.</p>
<p>Supplementary Figure S3 shows confirmation of AKT expression and knockdown in additional cell lines. A, Immunoblotting analysis WM793 HT144 cells treated with each siRNA alone or combination showed effective individual paralogs using antibodies against total AKT1, AKT2, AKT3. B, Expression paralog MTG001 MTG004 RT-PCR.</p>
<p>Supplementary Figure S7 shows chemical structures of all pharmacological agents utilized in study, including MK2206, GSK2141795, GDC-0941, BYL719, RapaLink-1, GSK650394, GDC-0068, GDC-0084, and INY-03-041.</p>
<p>Supplementary Figure S6 shows that INY-03-041 leads to a substantial effect on melanoma cell proliferation but it is not as potent siAKT1-3. A, Cell confluency assay of MTG001 and MTG004 lines treated with DMSO control, GDC0068 (1µM), GDC0941 Lenalidomide or siAKT1-3 (50nM). Treatment led decreased (P < 0.0001 in each line), did lead death, similar MTG004. Lenalidomide, recruiter the E3 ubiquitin ligase Cereblon, conjugated form INY-03-041, was used negative control for...
<p>Supplementary Figure S1 shows that pharmacological inhibition of AKT has little effect on melanoma cells. Cell confluency assay under inhibition. A375, HT144, SK-MEL28, WM793, MTG001, and MTG004 cells were largely resistant to inhibitors MK2206 (2.5 µM) GDC0068 (1µM) while SK-MEL 28 MTG001 sensitive PI3Kα by GDC0941 (P < 0.001). Error bars indicate standard error the mean triplicate wells.</p>
<div>Abstract<p>Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 3 (AKT1–3) are <i>bona fide</i> oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition AKT1–3 melanoma cells. Although pharmacological was without effect,...
<p>Supplementary Figure S3 shows confirmation of AKT expression and knockdown in additional cell lines. A, Immunoblotting analysis WM793 HT144 cells treated with each siRNA alone or combination showed effective individual paralogs using antibodies against total AKT1, AKT2, AKT3. B, Expression paralog MTG001 MTG004 RT-PCR.</p>