All Publications


  • Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells. Frontiers in oncology Tucci, J., Chen, T., Margulis, K., Orgel, E., Paszkiewicz, R. L., Cohen, M. D., Oberley, M. J., Wahhab, R., Jones, A. E., Divakaruni, A. S., Hsu, C., Noll, S. E., Sheng, X., Zare, R. N., Mittelman, S. D. 2021; 11: 665763

    Abstract

    Background: There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.Methods: We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.Results: Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.Conclusion: These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.

    View details for DOI 10.3389/fonc.2021.665763

    View details for PubMedID 33968771

  • Nanoparticles decorated with granulocyte-colony stimulating factor for targeting myeloid cells. Nanoscale Margulis, K., Honkala, A., Kalashnikova, I., Noll, S. E., Hill, M., Zare, R. N., Smith, B. R. 2020

    Abstract

    Dysregulated myeloid cell activity underlies a variety of pathologies, including immunosuppression in malignant cancers. Current treatments to alter myeloid cell behavior also alter other immune cell subpopulations and nonimmune cell types with deleterious side effects. Therefore, improved selectivity of myeloid treatment is an urgent need. To meet this need, we demonstrate a novel, targeted nanoparticle system that achieves superior myeloid selectivity both in vitro and in vivo. This system comprises: (1) granulocyte-colony stimulating factor (G-CSF) as a targeting ligand to promote accumulation in myeloid cells, including immunosuppressive myeloid-derived suppressor cells (MDSCs); (2) albumin nanoparticles 100-120 nm in diameter that maintain morphology and drug payload in simulated physiological conditions; and (3) a fluorophore that enables nanoparticle tracking and models a therapeutic molecule. Here, we show that this strategy achieves high myeloid uptake in mixed primary immune cells and that nanoparticles successfully infiltrate the 4T1 triple-negative breast tumor murine microenvironment, where they preferentially accumulate in myeloid cells in a mouse model. Further development will realize diagnostic myeloid cell tracking applications and therapeutic delivery of myeloid-reprogramming drugs.

    View details for DOI 10.1039/c9nr06494j

    View details for PubMedID 31956862

  • Using DESI-MSI to identify the genetic basis and tumorigenic mechanism of pheochromocytomas Noll, S., Armstrong, N., Margulis, K., Shankar, V., Storey, C., Kunz, P., Fishbein, L., Zare, R., Annes, J. AMER CHEMICAL SOC. 2019