Ying Yan, PhD

Ying Yan, PhDAssistant Professor

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General Research Interests
Cell signaling pathways in oncogenesis and cancer metastasis
Protein phosphatases and kinases
Cell cycle regulation, DNA damage checkpoint response and stress-induced cellular aging

PP2A Ser/Thr phosphatase in pancreatic cancer
Pancreatic cancer is one of the most lethal cancers. Despite extensive research, there are no effective targeted therapies for this disease. While almost all the signaling networks implicated in cancer rely on the cooperation of kinases and phosphatases to transduce signals promoting cancer, most efforts have only been put on the study of protein kinases in cancer while leaving protein phosphatases as a blind spot. PP2A is a family of heterotrimers that serve as the main source of Ser/Thr phosphatase activities in human cells. A PP2A complex consists of a scaffold subunit, a catalytic subunit, and one of many non-conserved regulatory subunits (>27), which determine the PP2A substrate specificities. Our studies have identified PR55α, a regulatory subunit of PP2A, as an important new player in promoting pancreatic cancer. Our studies revealed that PR55a inhibits the Hippo tumor suppression pathway and activates YAP oncogenic signaling in pancreatic cancer. In line with the essential role of YAP signaling in Kras-driven pancreatic cancer development and progression, knockdown of PR55α impedes the tumorigenicity and metastasis of pancreatic cancer cells. Our studies also revealed that PR55α stability is negatively controlled by the p53 tumor suppressor through its target gene FBXL20, which serves as a substrate adaptor for the SCF (SKP1-CUL1-F-box protein) E3 ligase that promotes proteasomal degradation. Currently, we are pursuing the following studies: (1) determining the mechanism by which p53 suppresses PR55α, (2) delineating the mechanism by which PR55α/PP2A promotes YAP activation, and (2) assessing the contribution of PR55α/PP2A to pancreatic cancer tumorigenesis and progression.

Development of new chemotherapeutics for metastatic breast cancer
Ninety percent of breast cancer patients die because of metastatic breast cancer. Antimitotic agents emerged as some of the most successful anticancer drugs in the treatment of metastatic breast cancer. However, the efficacy of these drugs is frequently limited by the primary or acquired resistance and various side effects that can be severe, long-lasting, and often irreversible. Furthermore, the widespread use of these agents as the first-line therapy produces recurrent metastatic breast cancers from the cancer cells that survived previous exposure to these drugs, which makes them more chemoresistant than their parental cells. A quest for microtubule-targeting agents active in resistant breast cancer continues and the emphasis is on drugs that bind to the sites remote from taxane and vinca binding domains. N-[5-(3’-halobenzoyl)-1H-benzimidazol-2-yl]carbamates, the subject of this study, inhibit tubulin assembly by competing for the colchicine site. Binding to this remote site and clinically proven safety of these compounds inspired our efforts to develop on this platform an effective and safe breast cancer treatment. Our goal is to develop new treatments for metastatic breast cancer and reduce the mortality associated with metastatic breast cancer.

Targeting Rac1 for chemo/radio-sensitization of triple-negative breast cancer
Triple-negative breast cancer (TNBC) has the worst clinical outcome among all breast cancer subtypes. Because TNBC lacks the expression of ER, PR, and HER2 hormone receptors, there are no targeted therapies available for TNBC patients. Strategies that can improve the sensitivity of TNBC to existing chemo/radiation therapy are anticipated to reduce the rate of TNBC recurrence and improve patient survival. Chemo/radiation eradicate cancer cells mainly by causing DNA damage, whereases it also can activate prosurvival signaling pathways, notably the ATM/ATR, ERK, and NFkB, pathways that are known to promote DNA repair, inhibit apoptosis, and/or preserve cancer stem cells. Our studies identified that Rac1, a membrane-bound GTPase, is overexpressed in human TNBC. Furthermore, inhibition of Rac1 abrogates the activation of ATM/ATR, ERK, and NF-kB signalings and promotes apoptosis in TNBC cells treated with chemo/radiation. Consistently, inhibition of Rac1 in vivo sensitizes TNBC tumors to Adriamycin therapy in mouse models. This research project is to identify Rac1-mediated signaling pathways that promote TNBC cell survival in response to chemo/radiation and evaluate the chemo/radio-sensitizing activity of Rac1 inhibitors using preclinical studies in xenograft and transgenic mouse models of TNBC.

Publications
  1. Madduri LSV, Brandquist ND, Palanivel C, Talmon GA, Baine MJ, Zhou S, Johnson KR, Enke CA, Ouellette MM & Yan Y. p53/FBXL20 axis suppresses the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase. Neoplasia 2021. 23:1192–1203. PMC8570931
  2. Zhou S, Zheng D, Fan Q, Yan Y, Wang S, Lei Y, Besemer A, Zhou C & Enke CA Minimum Dose Rate Estimation for Pulsed FLASH Radiotherapy: A Dimensional Analysis. Medical Physics 47(7):3243-49
  3. Ouellette MM & Yan Y Radiation-activated prosurvival signaling pathways in cancer cells. Precision Radiation Oncology 3:111–20, DOI:10.1002/pro6.1076.
  4. Hein AL, Brandquist ND, Ouellette CY, Seshacharyulu P, Enke CA, Ouellette MM, Batra SK, & Yan Y PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells. Oncogenesis 8(11):63. PMC6817822
  5. Tian T, Bi CF, Hein AL, Zhang X, Wang C, Shen SF, Enke C, Vose J, Yan Y & Fu K Rac1 is a Novel Therapeutic Target in Mantle Cell Lymphoma. Blood Cancer Journal 8:17. PMC5809391.
  6. Burchett KM, Etekpo A, Batra SK, Yan Y & Ouellette MM Inhibitors of telomerase and poly(ADP-ribose)polymerases synergize to limit the lifespan of pancreatic cancer cells. Oncotarget 2017, 8(48): 83754-67. PMC3883701
  7. Seshacharyulua P, Baine MJ, Soucheka JJ, Menninga M, Kaura S, Yan Y, Ouellette MM, Jaina M, Lin C & Batra SK Biological determinants of radioresistance and their remediation in pancreatic cancer. Biochimica et Biophysica Acta (BBA) 2017, 1868(1): 69–92. PMC5548591
  8. Arnst JL, Hein AL, Taylor MA, Palermo NY, Contreras JI, Sonawane YA, Wahl AO, Ouellette MM, Natarajan A & Yan Y Discovery and Characterization of Small Molecule Rac1 Inhibitors. Oncotarget 2017, 8(21):34586-600. PMC5470993
  9. Hein AL, Seshacharyulu P, Rachagani S, Sheinin YM, Ponnusamy MP, Mumby MC, Ouellette MM, Batra SK & Yan Y PR55α subunit of protein phosphatase 2A supports the tumorigenic and metastatic potential of pancreatic cancer cells by sustaining hyperactive oncogenic signaling. Cancer Research 2016, 76(8):2243-53. PMC4873354
  10. Hein AL, Post CM, Sheinin YM, Lakshmanan I, Natarajan A, Enke CA, Batra SK, Ouellette MM & Yan Y RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment. Oncogene 2016, 35(49):6319-29. PMC5112160
  11. Yan Y, Hein A, Greer PM, Wang Z, Kolb RH, Batra SK & Cowan KH A novel function of HER2/Neu in the activation of G2/M checkpoint in response to g-irradiation. Oncogene 2015, 34(17):2215-26. PMC4362969.
  12. Seshacharyulu P, Ponnusamy MP, Rachagani S, Lakshmanan I, Haridas D, Yan Y, Ganti AK & Batra SK Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. Oncotarget 2015, 6(7):5164-81. PMC4467140
  13. Choi KH, Lakamp-Hawley AS, Kolar C, Yan Y, Borgstahl GEO & Ouellette MM The Oligonucleotide/Oligosaccharide Binding fold 1 (OB1) of human POT1 recognizes both telomeric and nontelomeric DNA motifs. Biochimie 2015, 115:17–27. PMC4500675
  14. Lakshmanan I., Seshacharyulu P., Haridas D., Rachagani S., Gupta S., Joshi S., Guda C., Yan Y, Jain M, Ganti AK, Ponnusamy MP & Batra SK Novel HER3/MUC4 oncogenic signaling exacerbates the tumorigenic phenotypes of pancreatic cancer cells. Oncotarget 2015, 6(25):21085-99. PMC4673252
  15. Yan Y & Ouellette MM Rac1 GTPase in pancreatic cancer. Aging 2015, 7(9): 609-10. PMC4600618.

URL to a complete list of my published work:
https://www.ncbi.nlm.nih.gov/myncbi/ying.yan.2/bibliography/public/

Current Support:
2021–2025  NIH/NIGMS/R01GM143329&
                      Title: PR55-alpha controlled PP2A in the regulation of the Hippo/YAP pathway
                      Principal Investigator: Ying Yan

2021–2024   U.S. Army/USAMRAA/CDMRP/W81XWH2110700  
                      Title: Effective oral benzimidazole carbamates for the treatment of metastatic breast cancer
                      Principal Investigator: Ying Yan

2021–2022   NE-DHHS (2022-59)
                      Title: Negative regulation of PR55α protein stability by p53 tumor suppressor
                      Principal Investigator: Ying Yan

2021-2022  University of Nebraska Collaboration Initiative Program - Pilot Project     
                      Title: Development of ultra-high dose-rate (FLASH) cancer radiotherapy
                      Principal Investigators: Ying Yan, Sumin Zhou, and Donald Umstadter (UNL)

2021–2022   Great Plains IDeA-CTR-Pilot Projects Program - Pilot Project               
                      Title: FLASH-radiation therapy for increasing therapeutic index of cancer treatment
                      Principal Investigators: Ying Yan, Sumin Zhou, and Donald Umstadter (UNL)

2021-2022 NE-DHHS (2022-42)                          
                     Title: Rho GTPases in the radioresponse of pancreatic cancer
                     Principal Investigator: Michel Ouellette
                     Role: Co-Investigator

2016-2022 NIH/NCI/R01CA206444                                            
                    Title: Rac1 GTPase in tumorigenesis and progression of pancreatic cancer
                    Principal Investigators: Michel M. Ouellette and Surinder K. Batra
                    Role: Co-Investigator  

Completed Research Support for the Last 5 Years

2014-2019  NIH/NCI/P50 CA127297                    
                      Title: SPORE in Pancreatic Cancer
                      Principal Investigator: Michael A. Hollingsworth
                      Role: Co-Investigator

2017-2018  Nebraska Center for Cellular Signaling (P30 GM106397) - Pilot Project                                                                             Title: Role of Rho GTPases in the radioresponse of pancreatic cancer
                     Principal Investigators: Michel M. Ouellette and Ying Yan

2015-2016  Nebraska Center for Cellular Signaling (P30 GM106397) - Pilot Project                                                                              Title: Targeting Rac1 for Sensitization of Breast Cancer to Radiation Therapy
                    Principal Investigators: Amarnath Natarajan and Ying Yan