Lily’s Science

Lily’s Science Portfolio

Transposon derived gene regulatory elements in cancer

There is global epigenetic dysregulation during transformation from normal to cancerous cells. One of the many consequences of this global epigenetic dysregulation is the reactivation of transposable elements (TEs). TEs compose roughly half of the human genome and are normally repressed through epigenetic mechanisms such as DNA methylation and histone modifications. Endogenous retroviruses (ERVs) are a class of TEs that contain long terminal repeats (LTRs) with putative gene regulatory motifs. LTRs can be co-opted to be pro-tumorigenic by becoming non-canonical promotors for oncogenic genes. While several examples of TE-derived promotors have been reported in cancer, the potential significance of TE-derived enhancers remains largely unexplored. Utilizing publicly available multi-omics datasets and molecular biology, Lily discovered several LTR families to have gene regulatory roles in cancers such as ovarian and colorectal cancer. Further evaluations of the regulatory role of these TE-derived enhancers will provide novel insights into cancer-related transcriptomes.

(Ivancevic et al, In revision, 2024. Nguyen et al, In preperation.)

Molecular underpinnings of bariatric surgery

The goal of this project was to determine whether the antidiabetic effects of bariatric surgeries – by far the most effective treatment for diabetes and obesity – was due to browning of adipose tissue. To accomplish this goal, bariatric surgeries were performed in mice and basal metabolic rates were measured using direct calorimetry. This work showed that bariatric surgery increased browning (metabolic rate) of white adipose tissues. This browning of white adipose tissue resulted in increased oxygen consumption and that conditional PRDM16 deletion (required for browning) ablated this increased metabolism.

(Holter et al, FASEB, 2020)

Development of Adipo-Clear

It is notoriously difficult to perform whole tissue imaging on fat tissues due to lipid interferance. This project aimed to develop a method used to clear, label, and image whole adipose tissues, termed Adipo-clear. With this technology, this body of work has shown that different regions of beige adipose tissues have distinct sympathetic neurite distribution.

 (Chi et al, Cell Metab, 2018)

Epigenetic therapy in therapy-resistant ovarian cancer

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. For her thesis project, Lily studied how inhibition of and epigenetic modifier, euchromatic histone methyltransferases 1 and 2 (EHMT1/2), can reduce tumor growth of PARPi-resistant disease. Using a wide range of computational and molecular biology methodologies, Lily discovered that EHMT1/2 inhibition robustly increases immune signaling pathways, transposable elements, and dsRNA formation. She also discovered that EHMT1/2 inhibition-mediated decrease of tumor growth is partially dependent on CD8 T cells. Altogether, her results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy.

(Nguyen et al, MCT, 2024. Nguyen et al, In revision, 2024)

Inositol 1,4,5-triphosphate receptor (InsP3R) in fatty liver disease

Aberrant calcium signaling has been linked to liver diseases such as non-alcoholic fatty liver disease. One of the main regulators of intracellular calcium in hepatocytes is the calcium release channels, InsP3R. This project examined how the predominant isoforms of calcium release channel InsP3R, InsP3RI (20-30%) and InsP3RII (~70%) affect metabolic homeostasis. This work has shown that although InsP3RII is the predominant form, depleting this channel in hepatocytes does not affect metabolic homeostasis. InsP3RI, on the other hand, seems to play a central role in lipid formation in hepatocytes.

(Feriod et al, AJP Endo, 2014. Feriod et al, Hep Comm, 2017)

Polycystin 2’s (PKD2) role in polycystic kidney disease

Polycystic kidney disease results from mutations in polycystin 1 and 2 (PKD1/2). While mutations in PKD1 have been extensively studied, less is known about PKD2, a calcium channel. This project examined the role of PKD2 in the renal and extra-renal pathogenesis of polycystic kidney disease. This work has shown that aberrant calcium signaling due to PKD2 deletion results in cyst formation in kidneys and altered cardiac contractility in the heart.

(Kuo et al, PNAS, 2014. Kuo et al, PNAS, 2014; Kuo et al, PLoS One, 2016)

Lily’s Science Publications

In revision

  1. Nguyen, L. L., et al. “EHMT/G9A inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.”

  2. Pasquesi GIM, Allen H, Ivancevic A, Barbachano-Guerrero A, Joyner O, Guo K, Simpson DM, Gapin K, Horton I, Nguyen L, Yang Q, Warren CJ, Florea LD, Bitler BG, Santiago ML, Sawyer SL, Chuong EB. Regulation of human interferon signaling by transposon exonization. bioRxiv (2023) doi: 10.1101/2023.09.11.557241

  3. Ivancevic A, Simpson DM, Joyner OM, Bagby SM, Nguyen LL, Bitler BG, Pitts TM, Chuong EB. Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer. bioRxiv (2021) doi:10.1101/2021.10.28.466196

Published

  1. Nguyen, L. L., Watson, Z. L., Ortega, R., Woodruff, E. R., Jordan, K. R., Iwanaga, R., Yamamoto, T. M., Bailey, C. A., To, F., Jeong, A. D., Guntupalli, S. R., Behbakht, K., Gibaja, V., Arnoult, N., Cocozaki, A., Chuong, E. B., & Bitler, B. G. (2024). Combining EHMT and PARP Inhibition: A Strategy to Diminish Therapy-Resistant Ovarian Cancer Tumor Growth while Stimulating Immune Activation. Molecular Cancer Therapeutics. https://doi.org/10.1158/1535-7163.MCT-23-0613

  2. McMellen, A., Yamamoto, T. M., Qamar, L., Sanders, B. E., Nguyen, L. L., Ortiz Chavez, D., Bapat, J., Berning, A., Post, M. D., Johnson, J., Behbakht, K., Nurmemmedov, E., Chuong, E. B., & Bitler, B. G. (2023). ATF6-Mediated Signaling Contributes to PARP Inhibitor Resistance in Ovarian Cancer. Molecular Cancer Research: MCR, 21(1), 3–13. https://doi.org/10.1158/1541-7786.MCR-22-0102

  3. Holter, M. M., Garibay, D., Lee, S. A., Saikia, M., McGavigan, A. K., Nguyen, L., Moore, E. S., Daugherity, E., Cohen, P., Kelly, K., Weiss, R. S., & Cummings, B. P. (2020). Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 34(1), 1846–1858. https://doi.org/10.1096/fj.201902214R

  4. Chi, J., Wu, Z., Choi, C. H. J., Nguyen, L., Tegegne, S., Ackerman, S. E., Crane, A., Marchildon, F., Tessier-Lavigne, M., & Cohen, P. (2018). Three-Dimensional Adipose Tissue Imaging Reveals Regional Variation in Beige Fat Biogenesis and PRDM16-Dependent Sympathetic Neurite Density. Cell Metabolism, 27(1), 226-236.e3. https://doi.org/10.1016/j.cmet.2017.12.011

  5. Feriod, C. N., Oliveira, A. G., Guerra, M. T., Nguyen, L., Richards, K. M., Jurczak, M. J., Ruan, H.-B., Camporez, J. P., Yang, X., Shulman, G. I., Bennett, A. M., Nathanson, M. H., & Ehrlich, B. E. (2017). Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver. Hepatology Communications, 1(1), 23–35. https://doi.org/10.1002/hep4.1012

  6. Kuo, I. Y., Duong, S. L., Nguyen, L., & Ehrlich, B. E. (2016). Decreased Polycystin 2 Levels Result in Non-Renal Cardiac Dysfunction with Aging. PloS One, 11(4), e0153632. https://doi.org/10.1371/journal.pone.0153632

  7. Feriod, C. N., Nguyen, L., Jurczak, M. J., Kruglov, E. A., Nathanson, M. H., Shulman, G. I., Bennett, A. M., & Ehrlich, B. E. (2014). Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is reduced in obese mice, but metabolic homeostasis is preserved in mice lacking InsP3R-II. American Journal of Physiology. Endocrinology and Metabolism, 307(11), E1057-1064. https://doi.org/10.1152/ajpendo.00236.2014

  8. Kuo, I. Y., Kwaczala, A. T., Nguyen, L., Russell, K. S., Campbell, S. G., & Ehrlich, B. E. (2014). Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways. Proceedings of the National Academy of Sciences of the United States of America, 111(46), 16604–16609. https://doi.org/10.1073/pnas.1415933111

  9. Kuo, I. Y., DesRochers, T. M., Kimmerling, E. P., Nguyen, L., Ehrlich, B. E., & Kaplan, D. L. (2014). Cyst formation following disruption of intracellular calcium signaling. Proceedings of the National Academy of Sciences of the United States of America, 111(39), 14283–14288. https://doi.org/10.1073/pnas.1412323111