A5061742422- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Regulation of Appetite and Obesity
- Cancer Cells and Metastasis
- RNA Research and Splicing
- Cancer Research and Treatments
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Protein Kinase Regulation and GTPase Signaling
- Metabolomics and Mass Spectrometry Studies
- Epigenetics and DNA Methylation
- Pharmacogenetics and Drug Metabolism
- Adipokines, Inflammation, and Metabolic Diseases
- Cancer, Stress, Anesthesia, and Immune Response
- Ubiquitin and proteasome pathways
- Acute Myeloid Leukemia Research
- Peroxisome Proliferator-Activated Receptors
- Nanoplatforms for cancer theranostics
- RNA regulation and disease
- Immune cells in cancer
- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Adipose Tissue and Metabolism
- NF-κB Signaling Pathways
- Chronic Myeloid Leukemia Treatments
Larry Ellison Foundation
2022-2025
Ellison Institute of Technology
2022-2024
University of Southern California
2020-2023
University of Michigan
2012-2022
Cedars-Sinai Medical Center
2017-2018
Harvard University
2014
University of California, Los Angeles
2008
Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve factor (NGF). Targeted deletion Sh2b1 in mice results increased food intake, obesity, insulin resistance, with an intermediate phenotype seen heterozygous null on high-fat diet. We identified SH2B1 loss-of-function mutations large cohort patients severe early-onset obesity....
Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack understanding how these therapies affect unsuspecting bystanders stromal microenvironment. Cetuximab, monoclonal antibody therapy targeting epidermal growth factor receptor (EGFR), is given in combination with as standard care subset metastatic colorectal patients. The overall response to this treatment underwhelming and, while genetic mutations that confer resistance been...
Abstract Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation oncogenic transformation. We have extended these observations by investigating whether also non-histone proteins an additional mechanism linking its kinase activity development. now demonstrate EZH2 at T367 augment nuclear stabilization enzymatic cells. Consistent with this mechanistic role, DCAF1-mediated...
The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease myocardial infarction multiple genome-wide association studies. To investigate the role of Tm6sf2 metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated delivery. Hepatic overexpression mouse resulted phenotypes previously observed Tm6sf2-deficient including reduced lipid...
We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 by sequencing 500 severe early-onset obesity. has alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all As shown for past this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, individual exhibits...
Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance colorectal cancer (CRC). To exploit this crosstalk, we integrated systems biology approach that identified targets data-driven method validated them experimentally. This process involved novel machine learning-based computationally screen, high-throughput manner, the effects of enzyme perturbations predicted by computational model CRC metabolism. reveals...
Immune cell infiltrates (ICI) of tumors are scored by pathologists around tumor glands. To obtain a better understanding the immune infiltrate, individual types, their activation states and location relative to cells need be determined. This process requires precise identification area enumeration subtypes separately in stroma inside nests. Such measurements can accomplished multiplex format using immunohistochemistry (IHC). We developed pipeline that combines (IHC) digital image analysis....
The scaffold protein SH2B1, a major regulator of body weight, is recruited to the receptors multiple cytokines and growth factors, including nerve factor (NGF). β isoform but not α SH2B1 greatly enhances NGF-dependent neurite outgrowth PC12 cells. Here, we asked how unique C-terminal tails isoforms modulate function. We compared actions SH2B1α SH2B1β those N-terminal 631 amino acids shared by both isoforms. In contrast tail, tail inhibited ability cycle through nucleus enhance NGF-mediated...
The adapter protein SH2B1 is recruited to neurotrophin receptors, including TrkB (also known as NTRK2), the receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that four alternatively spliced isoforms of (SH2B1α-SH2B1δ) are important determinants neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1-/- [knockout (KO)] mice exhibit decreased neurite complexity length, BDNF-induced expression synapse-related immediate...
Abstract Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance colorectal cancer (CRC). To exploit this crosstalk, we integrated systems biology approach that identified targets data-driven method validated them experimentally. This process involved novel machine learning-based computationally screen, high-throughput manner, the effects of enzyme perturbations predicted by computational model CRC metabolism....
Abstract Patient-derived tumor organoids (PDTOs) have been shown to be predictors of clinical response. While evidence suggests PDTOs are a more physiologically relevant cell model use for drug discovery, challenges still exist fully characterize their response chemotherapies. Assays which attempt quantify in preclinical models often end-point and cannot separate responses heterogeneous cultures or capture dynamic information. Image based technologies counteract these shortcomings but...
Abstract The tumor microenvironment (TME) of colorectal cancer (CRC) plays an important role in progression and chemoresistance. Therefore, it is to incorporate elements the TME, such as extracellular matrix (ECM) composition stromal cells, into preclinical models better recapitulate dynamics vivo. Particularly, cancer-associated fibroblasts (CAFs) are a dominant cell type within TME that secrete remodel ECM whose abundance can correlate with poor overall survival. Patient-derived organoids...
Abstract Tumor-associated macrophages, a major stromal component within the tumor microenvironment (TME), play diverse roles in progression and response to therapy. Although their infiltration is linked unfavorable prognoses various cancer types, specific involvement colorectal (CRC) remains subject of debate. Within TME, macrophages can adopt pro-inflammatory (M1) or immune-suppressive (M2) phenotypes signals. In this study, we aimed investigate intricate interplay between CRC cells under...
Abstract Background: Prostate Cancer (PCa) is the most common non-skin cancer among American man. Currently, major challenges in clinical management of PCa include 1) a lack biomarkers that can reliably distinguish aggressive from indolent and 2) shortage therapeutic strategies prevent or suppress progression into PCa. Methods: Label-free quantitative proteomics was performed on three widely used cell lines with different levels aggressiveness (i.e., LNCaP, DU145 PC3). Upstream regulator...
Abstract Patient-derived tumor organoids (PDTOs) have recently been used as an innovative preclinical model to predict patient-specific drug responses. However, it is critical establish high quality, reproducible, and well-annotated PDTOs that closely recapitulate the original tumors from which they were derived. Here, we established a biobank of over 20 colorectal cancer (CRC) representing racially ethnically diverse patient population has subjected rigorous quality control (QC) measures....