Michelle Ozaki

All Publications

• Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ozaki, M. K., Zhang, Y., Bartlett, A. Q., de Wilde, E., Guan, X., Yang, A., Xia, Z., Schedin, P. 2025; 122 (24): e2420174122

  Abstract

  Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an enrichment of immune-suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver premetastatic niches. This work identifies features of reproductive control of liver biology that set a foundation for better understanding the potential role of the liver in maternal health.

  View details for DOI 10.1073/pnas.2420174122

  View details for Web of Science ID 001514348300001

  View details for PubMedID 40498462

  View details for PubMedCentralID PMC12184434

• Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes NATURE COMMUNICATIONS Jindal, S., Pennock, N. D., Sun, D., Horton, W., Ozaki, M. K., Narasimhan, J., Bartlett, A. Q., Weinmann, S., Goss, P. E., Borges, V. F., Xia, Z., Schedin, P. 2021; 12 (1): 6341

  Abstract

  Young women's breast cancer (YWBC) has poor prognosis and known interactions with parity. Women diagnosed within 5-10 years of childbirth, defined as postpartum breast cancer (PPBC), have poorer prognosis compared to age, stage, and biologic subtype-matched nulliparous patients. Genomic differences that explain this poor prognosis remain unknown. In this study, using RNA expression data from clinically matched estrogen receptor positive (ER+) cases (n = 16), we observe that ER+ YWBC can be differentiated based on a postpartum or nulliparous diagnosis. The gene expression signatures of PPBC are consistent with increased cell cycle, T-cell activation and reduced estrogen receptor and TP53 signaling. When applied to a large YWBC cohort, these signatures for ER+ PPBC associate with significantly reduced 15-year survival rates in high compared to low expressing cases. Cumulatively these results provide evidence that PPBC is a unique entity within YWBC with poor prognostic phenotypes.

  View details for DOI 10.1038/s41467-021-26505-3

  View details for Web of Science ID 000714451200022

  View details for PubMedID 34732713

  View details for PubMedCentralID PMC8566602

• Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer FRONTIERS IN ONCOLOGY Zeligs, K. P., Morelli, M., David, J. M., Neuman, M., Hernandez, L., Hewitt, S., Ozaki, M., Osei-Tutu, A., Anderson, D., Andresson, T., Das, S., Lack, J., Abdelmaksoud, A., Fantini, M., Arlen, P. M., Tsang, K. Y., Annunziata, C. M. 2020; 10: 805

  Abstract

  Purpose: Despite high initial response rates with cytoreductive surgery, conventional chemotherapy and the incorporation of biologic agents, ovarian cancer patients often relapse and die from their disease. New approaches are needed to improve patient outcomes. This study was designed to evaluate the antitumor activity of NEO-201 monoclonal antibody (mAb) in preclinical models of ovarian cancer where the NEO-201 target is highly expressed. Experimental Design: Functional analysis of NEO-201 against tumor cell lines was performed by antibody-dependent cellular cytotoxicity (ADCC) assays. Binding of NEO-201 to tumor tissues and cell lines were determined by immunohistochemistry (IHC) and flow cytometry, respectively. Further characterization of the antigen recognized by NEO-201 was performed by mass spectrometry. Ovarian cancer models were used to evaluate the anti-tumor activity of NEO-201 in vivo. NEO-201 at a concentration of 250 g/mouse was injected intraperitoneally (IP) on days 1, 4, and 8. Human PBMCs were injected IP simultaneously as effector cells. Results: Both IHC and flow cytometry revealed that NEO-201 binds prominently to the colon, pancreatic, and mucinous ovarian cancer tissues and cell lines. Immunoprecipitation of the antigen recognized by NEO-201 was performed in human ovarian, colon, and pancreatic cancer cell lines. From these screening, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 were identified as the most likely targets of NEO-201. Our results confirmed that NEO-201 binds different types of cancers; the binding is highly selective for the tumor cells without cross reactivity with the surrounding healthy tissue. Functional analysis revealed that NEO-201 mediates ADCC killing against human ovarian and colorectal carcinoma cell lines in vitro. In addition, NEO-201 inhibited tumor growth in the presence of activated human PBMCs in orthotopic mouse models of both primary and metastatic ovarian cancer. Importantly, NEO-201 prolonged survival of tumor-bearing mice. Conclusions: These data suggested that NEO-201 has an antitumor activity against tumor cells expressing its antigen. Targeting an antigen expressed in tumors, but not in normal tissues, allows patient selection for optimal treatment. These findings strongly indicate that NEO-201 warrants clinical testing as both a novel therapeutic and diagnostic agent for treatment of ovarian carcinomas. A first in human clinical trial evaluating NEO-201 in adults with chemo-resistant solid tumors is ongoing at the NIH clinical Center.

  View details for DOI 10.3389/fonc.2020.00805

  View details for Web of Science ID 000548399200001

  View details for PubMedID 32637350

  View details for PubMedCentralID PMC7318110

• Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model CANCERS Harrington, B. S., Ozaki, M. K., Caminear, M. W., Hernandez, L. F., Jordan, E., Kalinowski, N. J., Goldlust, I. S., Guha, R., Ferrer, M., Thomas, C., Shetty, J., Tran, B., Wong, N., House, C. D., Annunziata, C. M. 2020; 12 (6)

  Abstract

  Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.

  View details for DOI 10.3390/cancers12061645

  View details for Web of Science ID 000549348500001

  View details for PubMedID 32575908

  View details for PubMedCentralID PMC7352549

• Comparative Genomic Screen in Two Yeasts Reveals Conserved Pathways in the Response Network to Phenol Stress G3-GENES GENOMES GENETICS Alhoch, B., Chen, A., Chan, E., Elkabti, A., Farina, S., Gilbert, C., Kang, J., King, B., Leung, K., Levy, J., Martin, E., Mazer, B., McKinney, S., Moyzis, A., Nurimba, M., Ozaki, M., Purvis-Roberts, K., Rothman, J., Raju, S., Selassie, C., Smith, O., Ticus, J., Edwalds-Gilbert, G., Negritto, M., Wang, R., Tang, Z. 2019; 9 (3): 639-650

  View details for DOI 10.1534/g3.118.201000

  View details for Web of Science ID 000460596200004

• Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors JOURNAL OF CLINICAL INVESTIGATION Weiss, J. M., Davies, L. C., Karwan, M., Ileva, L., Ozaki, M. K., Cheng, R. Y. S., Ridnour, L. A., Annunziata, C. M., Wink, D. A., McVicar, D. W. 2018; 128 (9): 3794-3805

  Abstract

  Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset-specific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (Mϕ-specific) metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show that peritoneal tumors (B16 melanoma or ID8 ovarian carcinoma) elicited a fatty acid oxidation-mediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue-resident macrophages (pResMϕ). Unbiased metabolomics identified itaconic acid, the product of immune-responsive gene 1-mediated (Irg1-mediated) catabolism of mitochondrial cis-aconitate, among the most highly upregulated metabolites in pResMϕ of tumor-bearing mice. Administration of lentivirally encoded Irg1 shRNA significantly reduced peritoneal tumors. This resulted in reductions in OXPHOS and OXPHOS-driven production of ROS in pResMϕ and ROS-mediated MAPK activation in tumor cells. Our findings demonstrate that tumors profoundly alter pResMϕ metabolism, leading to the production of itaconic acid, which potentiates tumor growth. Monocytes isolated from ovarian carcinoma patients' ascites fluid expressed significantly elevated levels of IRG1. Therefore, IRG1 in pResMϕ represents a potential therapeutic target for peritoneal tumors.

  View details for DOI 10.1172/JCI99169

  View details for Web of Science ID 000443283400021

  View details for PubMedID 29920191

  View details for PubMedCentralID PMC6118601

• IKKε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts BMC CANCER House, C. D., Grajales, V., Ozaki, M., Jordan, E., Wubneh, H., Kimble, D. C., James, J. M., Kim, M. K., Annunziata, C. M. 2018; 18: 595

  Abstract

  Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC.Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition.This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins.This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.

  View details for DOI 10.1186/s12885-018-4507-2

  View details for Web of Science ID 000433334600002

  View details for PubMedID 29801480

  View details for PubMedCentralID PMC5970439

• NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH<SUP>+</SUP> Cancer Stem-like Cells CANCER RESEARCH House, C. D., Jordan, E., Hernandez, L., Ozaki, M., James, J. M., Kim, M., Kruhlak, M. J., Batchelor, E., Elloumi, F., Cam, M. C., Annunziata, C. M. 2017; 77 (24): 6927-6940

  Abstract

  Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NFκB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2 Interestingly, classical NFκB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NFκB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response. Cancer Res; 77(24); 6927-40. ©2017 AACR.

  View details for DOI 10.1158/0008-5472.CAN-17-0366

  View details for Web of Science ID 000418189800012

  View details for PubMedID 29074539

  View details for PubMedCentralID PMC5732863