A5078538809- Colorectal Cancer Treatments and Studies
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- PI3K/AKT/mTOR signaling in cancer
- 3D Printing in Biomedical Research
- Cancer Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Genetic factors in colorectal cancer
- Cancer Treatment and Pharmacology
- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- Cancer Immunotherapy and Biomarkers
- Chronic Lymphocytic Leukemia Research
- Neuroendocrine Tumor Research Advances
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Lung Cancer Research Studies
- Neuroblastoma Research and Treatments
- Immune cells in cancer
- Proteoglycans and glycosaminoglycans research
- Science, Research, and Medicine
- Chemical Reactions and Isotopes
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Biomedical Ethics and Regulation
University of Wisconsin Carbone Cancer Center
2015-2025
University of Wisconsin–Madison
2015-2025
Wisconsin Division of Public Health
2023-2024
Highland Community College - Illinois
2021
Madison Group (United States)
2019-2020
Center for Cancer Research
2007-2008
Leipzig University
1922
Cancer treatment is limited by inaccurate predictors of patient-specific therapeutic response. Therefore, some patients are exposed to unnecessary side effects and delays in starting effective therapy. A clinical tool that predicts sensitivity for individual needed.Patient-derived cancer organoids were derived across multiple histologies. The histologic characteristics, mutation profile, clonal structure, response chemotherapy radiation assessed using bright-field optical metabolic imaging...
New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform personalize treatments and discover novel therapies. Currently, methods evaluate drug response in limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of heterogeneity was characterized breast (BC) pancreatic (PC) patient-derived organoids. Baseline analyzed for each patient, demonstrating that...
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) account for roughly 60% of all tumors. Low/intermediate grade human GEP-NETs have relatively low proliferation rates that animal models and cell lines fail to recapitulate. Short-term patient-derived cancer organoids (PDCOs) are a 3D model system holds great promise recapitulating well-differentiated GEP-NETs. However, traditional measurements drug response (i.e., growth, proliferation) not effective in GEP-NET PDCOs due the small volume...
Abstract Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest targeting PI3K cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result constitutively active present subset pancreatic cancers. Here we examine mutant -mediated tumorigenesis response to dual PI3K/mammalian target rapamycin (mTOR) inhibition. Two murine models...
Therapeutic targeting of the PI3K pathway is an active area research in multiple cancer types, including breast and endometrial cancers. This commonly altered plays integral role numerous vital cellular functions. Mutations
290 Background: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) testing is a critical component of molecular for gastrointestinal cancers, among others. These analyses are important the identification patients with lynch syndrome and eligibility treatment immunotherapy. The current standard care can identify most cases, however improved MSI-H status needed non-colorectal cancers alterations outside MLH1/PMS2. A recent analysis indicated potential detection multiplex assay...
While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer (CRC), early-age-onset CRC (EAO CRC; age <50 years) has increased. Here, we characterize genetic alterations and tumor microenvironment (TME) for EAO later-age-onset (LAO) CRCs identify relevant biological differences that might point etiologic factors. A cohort (n = 60) LAO 93) patients were evaluated mutations by using targeted DNA sequencing TME immunohistochemistry...
Tumor heterogeneity is predicted to confer inferior clinical outcomes with precision-based strategies, however, modeling in a manner that still represents the tumor of origin remains formidable challenge. Sequencing technologies are limited their ability identify rare subclonal populations and predict response treatments for patients. Patient-derived organotypic cultures have significantly improved cancer biology by faithfully representing molecular features primary malignant tissues....
Abstract Background: The composition of the tumor microenvironment (TME) can regulate T cell infiltration and potentially immunotherapy efficacy. Versican (VCAN), an extracellular matrix proteoglycan, regulates presence infiltrating lymphocytes (TILs) their activation, while its proteolytic byproduct, versikine (Vkine), stimulate immune response. Here we aim to validate our prior findings that VCAN status correlates with CD8+ in intestinal cancers evaluate predictive role VCAN/Vkine for...
Abstract Background: Hyperactivation of PI3K has been linked to enhanced tumor cell growth and survival, highlighting its importance as a therapeutic target in colorectal cancer (CRC). In this study, we aim explore the effects STX-478, mutant-selective, allosteric PIK3CA inhibitor, assess impact on mutant CRC. Additionally, study aims investigate potential therapy combination with STX-478 that may amplify efficacy. A histone deacetylase romidepsin, was chosen interest due previous work shown...
Abstract Background: The PIK3CA gene, encoding the p110α protein, is commonly mutated across different cancer types, including colorectal (CRC). As 18% of CRCs have a mutation, more comprehensive understanding its influence on immune processes needed. Here we sought to isolate and characterize RNA expression signature mutant CRC at both tumor patient-derived organoid (PDCO) level. Methods: Patient/Originator Specimen (tumor) Organoid Culture sequencing data patients with without mutations...
Abstract Background: Versican (VCAN), a large chondroitin sulfate matrix proteoglycan is upregulated in the pancreatic ductal adenocarcinoma (PDAC) stroma and plays an immunosuppressive role. In contrast, VCAN V1 isoform can be cleaved by ADAMTS proteases 1, 4, 5, 9, 15 20 into fragment versikine which known to immunostimulatory. PDAC displays poor proteolysis CD8+ T-cell infiltration, but interestingly overexpresses 5 9. Alpha-2-macroglobulin (A2M) has been shown inhibit 4 may overexpressed...
Abstract Introduction: Co-alterations in PIK3CA (PK) and ARID1A (AD) occur ∼1% of all cancers. Previously we have shown that patients with mutations both genes are more sensitive to copanlisib (cop) treatment than those just PIK3CA(PK) mutation. Here evaluate the efficacy PI3K/AKT PI3K/mTOR dual inhibitors, compared cop using PKAD patient-derived cancer organoids (PDCOs). Methods: RSEM files from NCI repository were obtained for endometrial (EC) PDCOs PK, AD, wild type PK AD. Expression data...
Abstract Background: Patient derived cancer organoids (PDCOs) have shown to preserve cell morphology and better recapitulate patients’ cancers. Due these advantages, PDCOs could be used as a model predict how patient will respond drug treatments. STX-478, PIK3CAH1047R mutant specific inhibitor, has promise circumvent severe toxicities which aid in the tolerability of novel combinations. Here, we examine impact for predicting response chemotherapy discovery. Methods: PDCO lines were acquired...
Abstract Background: Versican is a large extracellular glycoprotein that acts as barrier for immune cell infiltration in colorectal cancer (CRC). The V1 isoform of versican can be cleaved by ADAMTS 4 and 5 into the bioactive fragment versikine with stimulatory properties. Despite overexpression CRC, may poorly proteolyzed. inhibited presence an endopeptidase inhibitor, alpha 2 macroglobulin (A2M). Here we investigate A2M expression its correlation proteolysis status, infiltration. Methods:...
Abstract Introduction: Tumor heterogeneity plays a major role in the development of resistance to therapies colorectal cancer (CRC). The epidermal growth factor receptor (EGFR) antibodies, panitumumab (pani) and cetuximab are commonly used for treatment CRC. At resistance, very low frequency KRAS mutations can be detected by circulating tumor DNA (ctDNA). This raises question if rare mutant clones lead EGFR inhibitor resistance. Here we utilized patient-derived organoids (PDCOs) investigate...
Background: Versican (VCAN) and its proteolysis product, Versikine (Vkine), have been shown to regulate CD8+ T-cell infiltration in cancers. Here, we evaluate the impact of VCAN accumulation on immune immune-related pathway expression across cancer types. Methods: RNA (Z-score) signatures VCANhi/ADAMTS4hi/TIMP3lo VCANhi/ADAMTS4lo/TIMP3hi were used identify proteolytic predominant (VPP) weak (VPW) cohorts, respectively, from TCGA Pan-cancer Atlas datasets. Gene-set enrichment analysis was...
Abstract Background: PIK3CA (PK) mutations occur in ∼18% of colorectal cancer (CRC) cases. However, an effective means to target these cancers clinic remains a challenge. Co-alterations and ARID1A (AD) ∼1% all The Z1F arm the NCI MATCH clinical trial demonstrated improved response rate for pan-PI3K inhibitor, copanlisib (cop) subjects with PK AD mutant cancers. Recent studies have shown that cop treatment leads p53 independent induction PUMA by FOXO3a CRC cell lines. Furthermore, is...
In colorectal cancer (CRC), attempts to identify cell-specific markers guide antibody-mediated therapeutics have failed uncover that are both exclusive tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which in the tumor microenvironment upregulate unique surface markers, not found healthy tissues. Here, we evaluated expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix...
The gut microbiota has a significant impact on the development and function of intestinal epithelial cells (IECs) by modifying bile acid (BA) metabolites. Recently, specific microbiome-derived BAs, such as 7-oxo-deoxycholic (7-oxo-DCA) isodeoxycholic (isoDCA), have been identified to be shifted inversely in colitis hepatic liver diseases. Although responsible microbes identified, metabolites’ effects IECs remain largely unclear. We found that although high-fat diet treatment mice elevated...
Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict exclusion CD8+ tumor-infiltrating lymphocytes (TILs) settings and, thus, is evaluated here. Methods: A total 230 cancers were analyzed for VCAN accumulation, proteolysis, and TILs. TILs categorized based on their...
The Apc(Min) mouse model of colorectal cancer provides a discrete, quantitative measurement tumor multiplicity, allowing for robust trait locus analysis. This advantage has previously been used to uncover polymorphic modifiers the Min phenotype: Mom1, which is partly explained by Pla2g2a; Mom2, spontaneous mutant modifier; and Mom3, was discovered in an outbred cross. Here, we describe localization novel modifier, Mom7, pericentromeric region chromosome 18. Mom7 mapped crosses involving four...
Abstract PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has be developed. MTORC1 inhibitors often used off-label for patients with mutant only limited data support this approach. Here we describe a cohort of treated possessing activating the PI3K signaling cascade minimal benefit treatment inhibitor everolimus. Previously, demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result...
Representative models are needed to screen new therapies for patients with cancer. Cancer organoids a leap forward as culture model that faithfully represents the disease. Mouse-derived cancer (MDCOs) becoming increasingly popular, however there has yet be standardized method assess therapeutic response and identify subpopulation heterogeneity. There multiple factors unique organoid could affect how MDCO heterogeneity assessed. Here we describe an analysis of nearly 3500 individual MDCOs...