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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2019)

Pancreatic cancers are notoriously aggressive and drug-resistant, and surgical resection is complicated by widespread intraperitoneal dissemination and ascites. One component of malignant ascites is lysophosphatidic acid (LPA), a bioactive lipid that promotes multiple aspects of tumor progression. Here, I report that expression of the cancer stem cell marker αvβ3 integrin is necessary and sufficient for the production of LPA. In turn, LPA was shown to induce the expression of stem genes OCT4 and NANOG and promote anchorage-independent growth. Upon interrogating the LPA metabolic pathway, I found that expression of αvβ3 integrin is necessary and sufficient to promote the expression of cytoplasmic phospholipase A2 (cPLA2), an important enzyme in the production of LPA. Furthermore, αvβ3 integrin forms a physical complex with cPLA2 to stabilize and stimulate its activity. Subsequently, KRAS mutant pancreatic cancer cells utilize LPA to overcome the effects of cellular stress, including cancer therapy. A variety of stress, including nutrient deprivation, oxidative stress, and treatment with standard-of-care chemotherapies, sensitizes cells to LPA-induced migration as well as KRAS-driven advantages such as macropinocytosis in response to nutrient stress and ROS elimination in response to oxidative stress. In order to cope with these stresses, cancer cells selectively upregulate the expression of LPA Receptor 4 (LPAR4). I illustrate that this receptor is necessary and sufficient for adaptation to stress in vitro and tumor progression in vivo. I showed that LPAR4 is necessary and sufficient to activate the Gαs/cAMP/PKA signaling pathway and that this pathway is required for LPA-mediated protection from stress. This is accomplished through activation of Vasodilator Stimulated Phosphoprotein (VASP), an enzyme involved in actin polymerization. Ultimately, I found that VASP is necessary for stress-mediated and LPAR4-mediate migration and macropinocytosis. My work highlights how stress changes the repertoire of LPA receptors, leading to dependence on LPAR4 by virtue of its stress mitigating functions, such as macropinocytosis and ROS elimination. Furthermore, my findings illustrate that αvβ3 integrin expressing cancer stem-like cells can secrete the bioactive lipid LPA through cPLA2 upregulation. Subsequently, cellular stress drives a more aggressive cancer phenotype by priming pancreatic cells to be highly responsive to LPA.

    Cover page: The combined role of stress and lysophosphatidic acid in pancreatic ductal adenocarcinoma progression
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5β1 or αVβ3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.
      Cover page: Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome are life threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high-value targets, including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development.
        Cover page: Cutaneous T-Cell Lymphoma PDX Drug Screening Platform Identifies Cooperation between Inhibitions of PI3Kα/δ and HDAC
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2015)

        Unlabelled

        There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies.

        Significance

        Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation.
          Cover page: Linking Tumor Mutations to Drug Responses via a Quantitative Chemical–Genetic Interaction Map
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