Saori Furuta, Ph.D.
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Saori Furuta, Ph.D. Assistant Professor Cancer Biology saori.furuta@utoledo.edu |
RESEARCH INTERESTS:
Over 300,000 new cases of breast cancer are diagnosed in the U.S. each year, affecting
1 in 8 women in their lifetime. Despite the recent advances in diagnostic tools, breast
cancer mortality rate has only declined slowly, justifying the urgent need for a better
diagnostic marker and treatment modality.
The long-term goal of our research is to determine the specific roles of tissue microenvironment
in regulating homeostasis vs. precancerous progression of the breast as well as therapeutic
resistance. In particular, we are investigating how disrupted nitroso-redox balance
influences different components of tissue microenvironment (e.g., extracellular matrix
(ECM), fibroblasts, macrophages and secreted cytokines) and contributes to cancer
initiation/progression and therapeutic resistance.
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| Fig. 1. Normal vs. malignant breast tissues staining for S-nitrosocysteine, the marker for nitric oxide. |
There are four on-going relevant projects in the laboratory:
1. Determine how deficiency of nitric oxide upregulates HER2 and TGFß and induces precancerous
lesions in mammary glands.
We previously found that the level of nitric oxide (NO) plummets during breast cancer
progression in parallel to reduction of tetrahydrobiopterin (BH4, the essential cofactor of NO synthase). Pharmacological deprivation of NO in wild-type
animals induced desmoplastic fibrous ECM and precancerous mammary lesions that overexpressed
HER2 and TGFß. On the other hand, restoration of the basal NO level in panel of breast
cancer cell lines with sepiapterin (the precursor of BH4) suppressed their growth by inhibiting the expression of HER2 and TGFß. We hypothesize
that NO helps suppress the expression of HER2 and TGFß through S-nitrosylation (SNO,
NO-mediated modification of certain cysteines), whereas NO deficiency deprives SNO,
unleashing these two tumorigenic proteins (Fig. 2). The current project is first to
identify the SNO sites in HER2 and TGFß, as well as their upstream regulators, and
the pathogenic relevance of defective SNO to precancerous progression of the breast.
Then, we will test the utility of SNO of these proteins as biomarkers in precancerous
human tissues. 
Fig. 2. Working model
for SNO-mediated suppression
of the expression
of HER2 and TGFß and HER2 in
normal breast cells.
2. Determine the therapeutic efficacy of sepiapterin (the precursor of BH4, the essential cofactor of NO synthase) in suppressing the growth of HER2-positive
mammary tumors in animals.
We previously found that reduction of NO during breast cancer progression was correlated
to the dramatic decrease of tetrahydrobiopterin (BH4), the redox-sensitive, essential cofactor of NO synthase (NOS), under increased oxidative
stress. We then administered sepiapterin, the precursor of BH4, to a panel of different breast cell lines in 3D ECM cultures and found that sepiapterin
treatment led to a dramatic decline (60-90%) of proliferation of cancer cells without
affecting normal cells. The current project is to test whether sepiapterin (alone
or in combination with anti-angiogenic drugs) could ameliorate the growth of HER2-positive
mammary tumors in animals.
Fig. 3. Working model
for M1-to-M2 conversion of
macrophages by sepiapterin,
the precursor of BH4,
the essential cofactor
of NO synthase.
3. Determine whether sepiapterin could reprogram M2 to M1 macrophages, improving
the immunotherapy for breast cancer.
Previous studies showed that BH4 level is differentially modulated during macrophage polarization because of differential
levels of GCH1, the rate-limiting enzyme of de novo biosynthesis of BH4. BH4 levels become extremely high during M1 polarization, whereas it becomes almost undetectable
during M2 polarization. We hypothesize that administration of sepiapterin, an intermediate
of the salvage pathway of BH4, to M2 macrophage will induce reprogramming of M2 to M1 macrophages (Fig. 3). Our
preliminary results showed that administration of sepiapterin to M2-polarized THP-1
cells induced their conversion to M1 type in culture. The current project is to test
whether this phenomenon could be observed in M2-polarized primary macrophages in culture
and in mice bearing HER2-positive mammary tumors.
4. Generate and determine the efficacy of liposomes-based delivery system of sepiapterin
that specifically targets HER2-positive cancer cells.
We previously found that sepiapterin treatment conferred strong (60~90%) growth suppression
of different breast cancer cells in culture even after 2 hours of treatment. On the
contrary, previous studies by another group showed that systemic administration of
sepiapterin in animals suppressed the growth of HER2-positive mammary tumors by as
much as 20%. Because the same group also reported that sepiapterin conferred strong
angiogenetic stimuli to tumor vasculature, this might have dampened the anti-tumor
effect of the drug. While testing the anti-tumor effect of the combinatorial treatment
of sepiapterin and anti-angiogenic drugs (project #2 above), we are also generating
liposomes that specifically deliver sepiapterin to HER2-positive cancer cells. The
liposomes enclose sepiapterin and are loaded with HER2-binding peptide (Herceptin
analog) and fluorophores excited at near-infrared wavelength to generate fluorescence
as well as heat (photothermal therapy) (Fig. 4). We will test the efficacy of drug-delivery,
stability and anti-tumor activities of liposomes using mice bearing HER2-positive
mammary tumors. We hypothesize that this liposome-based drug delivery, combined with
photothermal therapy, will specifically target and effectively kill HER2-positive
mammary tumors.
Fig. 4. HER2-targeting
liposome loaded with
near-infrared fluorophore
and sepiapterin.
To implement these projects, we utilize a high-resolution image technique, including
second harmonics generation on multiphoton microscope, time-lapse confocal microscopy
and atomic force microscopy, as well as animal studies, mass spectrometry, 3D cultures
(mono and co-cultures), histological studies of clinical samples and other molecular/cell
biology/biochemistry techniques.
Dr. Furuta is a member of the faculty in the Biomedical Sciences Graduate Program,
Cancer Biology track.
EDUCATION:
Postdoc 2007-2014, Life Sciences Division, Lawrence Berkeley National Laboratory,
Berkeley, CA
Ph.D. 2007, University of California, Irvine
M.S. 2001, California State University, Los Angeles
B.S. 1999, University of California, Riverside
ACADEMIC APPOINTMENTS:
2015-present Assistant Professor, Dept. Cancer Biology, University of Toledo College
of Medicine & Life Sciences, Toledo, OH
2015-present Affiliate, Biological Systems and Engineering Division, Lawrence Berkeley
National Laboratory, Berkeley, CA
2014-2015 Project Scientist, Life Sciences Division, Lawrence Berkeley National
Laboratory, Berkeley, CA
REPRESENTATIVE PUBLICATIONS:
Makmura, L., Hamann, M., Areopagita, A., Furuta, S., Munoz, A., Momand, J. Development of sensitive assay to detect reversibly oxidized protein cysteine sulfhydryl
groups. Antioxid. Redox Signal 2001; 3(6):1105-18. PMID: 11813984
Furuta, S., Ortiz, F., Zhu, Sun X., Wu, HH., Mason, A., Momand, J. Copper uptake is required for pyrrolidine dithiocarbamate-mediated oxidation and protein
level increase of p53 in cells. Biochem. J. 2002; 365(Pt 3):639-48. PMC1222712
Utomo, A., Jiang, X., Furuta, S., (first three contributed equally) Yun, J., Levin, D.S., Wang,Y.C., Desai, K.V., Green,
J.E., Chen, P.L., Lee, W.H. Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide
glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated
from polyunsaturated fatty acids in breast cancer cells. J Biol Chem. 2004; 279(42):43522-9. PMID: 15294905
Furuta, S., Jiang, X., Gu, B, Cheng, E., Chen, P.L., Lee, W.H. Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial
cells. Proc Natl Acad Sci U S A. 2005; 102(26):9176-81. PMC1166629
Momand, J., Aspuria, P.J., Furuta, S. “MDM2 and MDMX-regulators of p53 activity”, a chapter in Protein Reviews Vol 2:
The p53 Tumor Suppressor Pathway and Cancer 2005; pp155-186. Kluwer Academic/Plenum
Publishers (New York, NY).
Furuta, S., Wang, J., Shuanzeng, W., Jeng, Y.M., Jiang, X., Gu, B., Chen, P.L., Lee, E.Y.H.P.,
Lee, W.H. Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated breast tumor growth contributed by prominent vasculature. Cancer Cell 2006; 10(11):13-24. PMID: 16843262
Jeng, Y.M., Cai, S., Li, A., Furuta, S., Chen, P.L., Lee, E.Y.H.P., Lee, W.H. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis
with haploinsufficiency upon ionizing irradiation. Oncogene 2007; 24(42):6160-6. PMID: 17420720
Furuta, S., Jeng, Y.M., Zhou, L., Huang, L., Kuhn, I., Bissell, M.J., Lee, W.H. IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to
nonmalignant cells. Sci Transl Med. 2011; 3(78):78ra31. PMC3199022
Furuta, S., Ghajar, C.M., Bissell, M.J. Caveolin-1: Would-be Achilles’ heel of tumor microenvironment? Cell Cycle 2011; 10:1794-1809. PMID: 22030625
Ordinario, E., Han, H.J., Furuta, S., Heiser, L., Jakkula, L., Rodier, F., Spellman, P., Campisi, J., Gray, J., Bissell,
M.J., Kohwi, Y., Kohwi-Shigematsu, T. ATM suppresses SATB1-induced malignant progression in breast epithelial cells. PLOS One 2012;7(12):e51786. PMC3519734
Lee, S-Y., Meier, R., Furuta, S. (first three contributed equally; SF serves as a co-corresponding author with MJB), Lenburg, M.E., Kenny, P.A., Xu, R., Bissell, M.J. FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J. Clin. Invest. 2012; 122(9):3211-3220. PMC3428077
Becker-Weimann, S., Xiong, G., Furuta, S., Han, J., Kuhn, I., Akavia, U.D., Pe’er, D., Bissell, M.J., Xu, R. NF-kappaB integrates microenvironmental signals that disrupt tissue polarity and induce
cell invasion in breast cancer cells. Oncotarget 2013; 4(11):2010-2010. PMC3875766
Furuta, S., Bissell, M.J. (2016) Pathways involved in dormation of mammary organoid architecture have keys to understanding
drug resistance and to discovery of druggable targets. Cold Spring Harb Symp Quant Biol., 2016; 81:207-217. PMID: 28416576
Furuta, S.*, Ren, G., Mao, J.H., Bissell, M.J., Laminin signals initiate the receiprocal loop that informs breast-specific gene expression
and homeostasis by activating NO, p53 and microRNAs. eLife 2018; 7:e26148. PMCID: PMC5862529.
(*SF also serves as a co-corresponding author with MJB)
Ricca, B.L., Venugopalan, G., Furuta, S., Tanner, K., Orellana, W.A., Reber, C.D., Brownfield, D.G., Bissell, M.J., Fletcher,
D.A. Transient external force induces phenotypic reversion of malignant epithelial structures
via nitric oxide signaling. eLife 2018; 7:e26161. PMCID: PMC5862525.
Ren, G., Zheng, X., Bommarito, M., Metzger, S., Letson, J., Walia, Y., Furuta, S. Reduced basal nitric oxide production induces precancerous mammary lesions via ERBB2
and TGFß. Sci. Rep., in revision.