A5077659587- Pancreatic and Hepatic Oncology Research
- Advanced Breast Cancer Therapies
- Colorectal Cancer Treatments and Studies
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Neuroendocrine Tumor Research Advances
- Growth Hormone and Insulin-like Growth Factors
- Protein Kinase Regulation and GTPase Signaling
- Cancer Mechanisms and Therapy
- Melanoma and MAPK Pathways
- Pancreatic function and diabetes
- Endoplasmic Reticulum Stress and Disease
- Cancer Genomics and Diagnostics
- Cancer Research and Treatments
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Caveolin-1 and cellular processes
- Cancer-related Molecular Pathways
- Metabolism, Diabetes, and Cancer
- Biochemical and Molecular Research
- Cellular transport and secretion
- Phagocytosis and Immune Regulation
- MicroRNA in disease regulation
University of North Carolina at Chapel Hill
2016-2025
UNC Lineberger Comprehensive Cancer Center
2015-2024
Segeberger Kliniken
2024
Cornell University
2011-2015
Tumor progression involves the ability of cancer cells to communicate with each other and neighboring normal in their microenvironment. Microvesicles (MV) derived from human have received a good deal attention because participate horizontal transfer signaling proteins between contribute invasive activity. Here we show that MV may play another important role oncogenesis. In particular, demonstrate shed by two different cells, MDAMB231 breast carcinoma U87 glioma are capable conferring onto...
Abstract Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether functionally distinct from more KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). found KRASG12D/V but not drives...
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation KRAS in promoting the development and malignant growth pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration p16INK4A with inhibitors CDK4 CDK6 (CDK4/6) has shown limited clinical efficacy PDAC. Here, we found concurrent treatment both CDK4/6 inhibitor (CDK4/6i) an ERK-MAPK (ERKi) synergistically suppresses PDAC cell lines organoids by cooperatively...
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To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing...
Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development improved therapies. As KRAS mutations are found in 95% PDAC and critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. macrometabolic process autophagy is upregulated KRAS-mutant PDAC, growth reliant on autophagy. However, inhibition as monotherapy using lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy....
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients advanced unresectable PDAC restricted to systemic chemotherapy, intervention which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added the arsenal first-line therapies, combination gemcitabine n-PTX modestly prolonged median overall survival. However, almost invariably succumb...
Mutations in KRAS frequently occur human cancer and are especially prevalent pancreatic ductal adenocarcinoma (PDAC), where they have been shown to promote aggressive phenotypes. However, targeting this onco-protein has proven be challenging, highlighting the need further identify various mechanisms used by drive progression. Here, we considered role played exosomes, a specific class of extracellular vesicles (EVs) derived from endocytic cellular trafficking machinery, mediating ability cell...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux dependency, concurrent treatment with nonspecific autophagy inhibitor chloroquine (CQ) ERK-MAPK inhibitors can synergistically block PDAC However, CQ limited in terms specificity potency. To find alternative anti-autophagy strategies, here we performed a CRISPR-Cas9 loss-of-function screen cell lines that identified...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by activating mutations in KRAS, which promote tumor progression through sustained activation of the MAPK (RAS/RAF/MEK/ERK) signaling pathway. This study investigates metabolic vulnerabilities associated with PDAC examining reprogramming that occurs upon KRAS inhibition via targeting MEK/ERK/KRASG12D, and utilizing metabolomic, lipidomic, isotope-tracing approaches. Our findings reveal MEK/ERK/KRASG12D results enhanced...
Abstract Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in cancers harboring genomic deletions of the MTAP gene, which encodes enzyme methylthioadenosine phosphorylase. Approximately one four pancreatic ductal adenocarcinoma (PDAC) cases harbor homozygous deletion gene (MTAP-del), providing promising novel targeted therapy for PDAC. The (MTA)-cooperative PRMT5 inhibitor BMS-986504 (previously known as MRTX1719) leverages elevated MTA levels present MTAP-del tumors...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because rapid acquisition tumor-intrinsic resistance. However, the unique PDAC TME may also be driver We found long-term focal adhesion (FAK) inhibitor treatment led...
The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC essential for malignant transformation. key to oncogenic working together stabilization of expression due activating extracellular signal-regulated kinase 1/2, which phosphorylates at serine 62 (Ser 62). This prevents proteasomal degradation while enhancing transcriptional activity. Here, we identify how this signaling connection between mediated by inhibitor apoptosis...
Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of events oncogenic KRAS could enhance therapeutic approaches. Here we analyzed the basal CpG 11 KRAS-mutant and dependent pancreatic cancer cell lines observed strikingly similar patterns. knockdown resulted unique...