A5004350870- Cancer Mechanisms and Therapy
- Lung Cancer Treatments and Mutations
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- Synthesis and biological activity
- Biochemical and Molecular Research
- Phagocytosis and Immune Regulation
- RNA modifications and cancer
- Cancer Cells and Metastasis
- Molecular Biology Techniques and Applications
- Protein Tyrosine Phosphatases
- Nuclear Receptors and Signaling
- Mechanisms of cancer metastasis
- Cancer-related Molecular Pathways
- Lung Cancer Research Studies
- Histone Deacetylase Inhibitors Research
- Cancer therapeutics and mechanisms
- Genomics and Phylogenetic Studies
- Pancreatic and Hepatic Oncology Research
- RNA and protein synthesis mechanisms
- Congenital heart defects research
- Caveolin-1 and cellular processes
- Chemical Reactions and Isotopes
- Wnt/β-catenin signaling in development and cancer
- Cancer-related molecular mechanisms research
Elements Biosciences (United States)
2023
Biospyder (United States)
2018-2019
University of California, San Francisco
2012-2019
UCSF Helen Diller Family Comprehensive Cancer Center
2012-2019
Salk Institute for Biological Studies
2013-2018
Peter MacCallum Cancer Centre
2012-2013
The University of Melbourne
2013
McGill University
2012
Oregon Health & Science University
2012
Stanford University
2012
KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance critical to improve treatment this disease. Here, we show that expression BRAF(V600E), not PIK3CA(H1047R), in the mouse pancreas leads intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant BRAF(V600E) TP53(R270H) result lethal PDA. We tested inhibitors effectors against...
The mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge developmental kinetics mechanisms lineage specification is lacking. We address this significant gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, adult mouse development. From these data, we map the chronology transcriptionally epigenetically distinct cell states distinguish fetal stem (fMaSCs) from...
To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks are present the stem cells responsible for fetal and adult development. These analyses identified a axis between FGF transcription factor Sox10. Here, show Sox10 is specifically expressed exhibiting highest levels of stem/progenitor activity. This includes vivo organoids vitro. functionally relevant, as its deletion reduces competence whereas overexpression increases Intriguingly, also causes...
Abstract Genetically engineered mouse (GEM) models of lung tumorigenesis allow careful evaluation tumor initiation, progression, and response to therapy. Using GEM oncogene-induced cancer, we show the striking similarity earliest stages induced by KRASG12D or BRAFV600E. Cre-mediated expression BRAFV600E in epithelium adult mice initially elicited benign tumors comprising cuboidal epithelial cells expressing markers alveolar pneumocytes. Strikingly, a head-to-head comparison, oncogenic many...
We describe the use of a ligation-based targeted whole transcriptome expression profiling assay, TempO-Seq, to profile formalin-fixed paraffin-embedded (FFPE) tissue, including H&E stained FFPE by directly lysing tissue scraped from slides without extracting RNA or converting cDNA. The correlation measured gene changes in unfixed and fixed samples using blocks prepared pellet single cell type was R2 = 0.97, demonstrating that no significant artifacts were introduced fixation. Fixed fresh an...
Abstract Adenocarcinoma of the lung, a leading cause cancer death, frequently displays mutational activation KRAS proto-oncogene but, unlike lung cancers expressing mutated EGFR, ROS1, or ALK, there is no pathway-targeted therapy for patients with KRAS-mutated cancer. In preclinical models, expression oncogenic KRASG12D in epithelium adult mice initiates development adenocarcinoma through downstream signaling pathways. contrast, mutationally activated BRAFV600E, effector, fails to initiate...
KRAS-activating mutations drive human non-small cell lung cancer and initiate tumorigenesis in genetically engineered mouse (GEM) models. However, a GEM model of KRAS(G12D)-induced cancer, tumors arise stochastically following latency period, suggesting that additional events are required to promote early-stage tumorigenic expansion KRAS(G12D)-mutated cells. PI3Kα (PIK3CA) is direct effector KRAS, but activation PI3'-lipid signaling may be potentiate KRAS-driven tumorigenesis. Using models,...
The search for the bipotent mammary stem cells that drive development requires markers to enable their prospective isolation. There is general agreement mouse are abundant in late fetal development, but existence adult vigorously debated. Among useful cell identification, Wnt co-receptor Lgr5 has been suggested by some be both "necessary and sufficient" bipotency transplantation of activity, though other studies disagree. Importantly, relevance not studied. We show here expression a...
Human lung adenocarcinoma exhibits a propensity for de-differentiation, complicating diagnosis and treatment, predicting poorer patient survival. In genetically engineered mouse models of cancer, expression the BRAFV600E oncoprotein kinase initiates growth benign tumors retaining characteristics their cell origin, AT2 pneumocytes. Cooperating alterations that activate PI3’-lipid signaling promote progression BRAFV600E-driven to malignant adenocarcinoma. However, mechanism(s) by which this...
Intra-tumoral heterogeneity complicates accurate diagnosis, reduces the effectiveness of precision therapeutics, and fuels metastatic dissemination. Discovering genes epigenetic mechanisms that produce developmentally plastic cells engender presents an important challenge need. As cancer is a caricature development, we used chromatin accessibility assays transcriptional profiling to infer pathways underlie lineage potential normal fetal adult mammary cell populations. We show basal share...
Abstract Profiling gene expression from small amounts of FFPE using methods that require extraction RNA the tissue, such as RNA-seq, have been problematic. We report use a modification whole transcriptome TempO-Seq® assay (Yeakley et al, PLOSone, 2017; DOI:10.1371/journal.pone.0178302) to profile 2 mm2 areas 5 μm thick sections by scraping tissue and assaying lysates directly without extracting RNA. Duration fixation amount sample down area do not impact performance assay. Good results can...
Abstract Basal-like breast cancers have unique characteristics that may contribute to their particularly poor prognosis. These include a high degree of genomic instability, intra-tumor heterogeneity, and gene expression profiles similar those normal mammary stem cells. arise through the aberrant propagation Alternatively, mutations commonly found in this subtype be dominant determinant tumor phenotype. In order explore these possibilities, pure populations cells need isolated analyzed. Our...
<p>Legends for Supplementary Figures S1-S9.</p>
<p>Comparison of ERK1/2 and AKT activation in KRASG12D- versus KRASG12D/PIK3CAH1047R-driven lung tumors.</p>
<p>Inhibitory effect of BYL719 on the growth orthotopic lung tumors defined Kras or Pik3ca genotype.</p>
<p>Inhibitory effects of pathway-targeted agents on the proliferation lung tumor derived cell lines defined Kras or Pik3ca genotype.</p>
<p>In vitro proliferation and cell signaling of lung tumor derived lines defined Kras or Pik3ca genotype.</p>
<p>Analysis of the consequences timing KRASG12D versus PIK3CAH1047R oncoprotein expression on lung tumorigenesis.</p>
<p>Orthotopic lung tumorigenesis following injection of tumor derived cell lines defined Kras or Pik3ca genotype.</p>
<p>Ex vivo analysis of KRASG12D- versus KRASG12D/PIK3CAH1047R-driven lung tumor cell proliferation in vibratome sections.</p>
<p>Inhibitory effects of BYL719 on tumorigenesis and signaling in human KRASQ61H/PIK3CAE545K-driven H460 lung cancer cells.</p>
<p>Pharmacodynamic analysis of the inhibitory effects BYL719 on pAKT in mice bearing KRASG12D/PIK3CAH1047R-driven lung tumors.</p>
Abstract Mammary stem cells (MaSCs) self-renew and generate the different epithelial cell types of breast. Impressively, a single MaSC can regenerate an entire functional mouse mammary gland when transplanted into cleared fat pad. Intriguingly, stem-like have been identified in some breast cancer using bioinformatic strategies. These observations raise number important questions: Do cancers arise by mutations occurring cells, as such high capacity for self-renewal, proliferation...