Pengrong Yan, PhD

Senior Research Scientist

Pengrong Yan, PhD

Senior Research Scientist
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Pengrong Yan, PhD

Lab Phone

646-888-2216

 

Graduate training: I was trained towards my PhD with Dr. Gutian Xiao at University of Pittsburgh School of Medicine. There I made mechanistic discoveries related to a role of autophagy and NF-kB in inflammation and cancer. My work was the first to provide evidence that an HSP90 client can be degraded by a mechanism different from the ubiquitin-proteasome pathway and to establish a molecular link among HSP90, NF-kB and autophagy. I also investigated the regulation of HTLV-I oncoprotein Tax by PDZ-LIM domain-containing protein (PDLIM2); specifically I identified PDLIM2 as a negative regulator of HTLV-I oncoprotein Tax. I found that the counterbalance between HTLV-I Tax and PDLIM2 determined the outcome of the HTLV-I infection. Furthermore, I defined the molecular determinants of PDLIM2 in suppressing Tax mediated tumorigenesis. By dissecting the functional sequences within PDLIM2 my work provided insights into the novel oncogenic mechanisms in HTLV-I leukemogenicity and cancer health disparities, and suggested potential therapeutic approaches against Adult T-cell Leukemia.

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Postdoctoral research: With my molecular biology and biochemistry credentials assured, I was recruited to be a member of Dr. Gabriela Chiosis’ laboratory at MSKCC after defending my PhD thesis. The interdisciplinary environment of the lab fostered my interest in chemical biology and translational research. My research moved to the understanding of how molecular chaperones aid in malignant transformation. I also developed a keen interest in the translation of mechanistic findings into novel therapies.

My first project had GRP94, the endoplasmic reticulum (ER) HSP90 paralog, the focus of my research. HSP90, the most abundant molecular chaperone in human cells has four paralogs. Whereas much work was dedicated to the study of the cytosolic HSP90 paralogs, HSP90α/β, little is known on molecular mechanisms associated with GRP94 in cancer. There is no GRP94 homolog in a genetically tractable organism such as yeast, and studies using mutant cell lines and gene-deficient mouse studies have been of limited use. To address this limitation, my lab created a variety of reagents and assays to enable the study of GRP94 in native tumors. I used these tools to find an unexpected role for GRP94 in cancer – cancer cells that activated signaling pathways through overexpression of receptor tyrosine kinases, translocated GRP94 to the plasma membrane and used it to regulate kinase activity at this location. My data indicated that only in cells with HER2 overexpression, the chaperoning function of GRP94 was vital for proper HER2 function. I also demonstrated that pharmacological inhibition of GRP94 in these cells was sufficient to destabilize membrane HER2, inhibit its signaling properties and target HER2 towards a degradative pathway. These findings were the first to implicate GRP94 in regulating oncogenic signal transduction at the plasma membrane. These effects were previously unknown and unanticipated although HER2 is a widely-studied HSP90 client protein. Also of importance, this work provided proof for the integration of the HSP90 chaperone system - when faced with an ‘over-demand’ from the proteome, in this case HER2 overproduction and enhanced HER2 signaling, the cancer cell brought in distinct HSP90 paralogs to cooperatively regulate HER2.

Over the past two years I made significant contributions to another major project in the lab. We found that cancer cells regulate proteome stress not only by chaperone overexpression, but rather by a re-wiring of the chaperone units. For example, in large proteome imbalances produced by MYC activation, we identified that cancer cells re-wire the majority of the chaperone units into large chaperone networks (Nature 2016). These networks, created by a change in the cellular milieu rather than defects in chaperone structure or expression, we term the epichaperome. These networks protect certain cancers against cell death during their transformation into malignancies. While chaperone units are abundant and expressed virtually in every cell in the human body, epichaperome networks are unique to cancer cells. When we looked for proteome stress that could create epichaperome, we recognized that cancer cells sensitive to chaperone inhibition had in common a MYC transcriptional signature. These cancer cells had indeed higher MYC transcriptional activity; and by turning MYC on, we could assemble the chaperome into epichaperome networks and make cancer cells sensitive to HSP90 inhibition. Conversely, by turning MYC off, we could dis-assemble the chaperome and make cancer cells insensitive.

In addition to providing a novel mechanism of tumor regulation, this work has two other major implications. First, it provides a means for precision chaperone therapy based not on genetics but rather on protein networks. We find that over half of cancers, irrespective of genetic defect, type, site or origin use epichaperome networks to regulate alterations in the proteome and maintain cellular survival. The finding provided a breaking-through point-of-view that revolutionized traditional paradigm that narrowly defines the drug selectivity by protein over-expression or mutations. We demonstrated that for a ubiquitously expressed chaperone (i.e. HSP90), drug sensitivity is not solely associated with its abundance, but rather determined by the binding affinity and interacting chaperome. Such discovery will prompt scientists to adopt a more dynamic view towards investigating cancer, rather than relying on static biomarkers. Second, it provides a means for building sequential combination therapies that incorporate HSP90 agents. A clinical study built on these findings is to start at MSKCC later this year.

Publications

  1. Li Y, Li Q, Zhang D, Jin W, Xu C, Sheng H, Liu Y, Lu G, Yu J, Yan P, Xie Y, Lu D, Nebert D, Harrison D, Huang W, and Jin L. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006, 116(2):506-11.
  2. Li Y, Shao C, Zhang D, Zhao M, Lin L, Yan P, Xie Y, Jiang K, and Jin L. The Effect of Dopamine D2, D5 Receptor and Transporter (SLC6A3) polymorphisms on the Cue-Elicited Heroin Craving in Chinese. Am J Med Genet B Neuropsychiatr Genet. 2006, 141(3):269-73.
  3. Qing G, Yan P, Qu Z, and Xiao G. Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IκB kinase. Cell Res. 2006, 16(11): 895-901. Also See Comment in Cell Res. 16(11): 855-56.
  4. Zhang D, Shao C, Shao M, Yan P, Wang Y, Liu Y, Liu W, Lin T, Xie Y, Zhao Y, Lu D, Li Y, and Jin L. Effect of Mu-Opioid Receptor Gene Polymorphisms on Heroin-Induced Subjective Responses in a Chinese Population. Biol Psychiatry. 2007, 61(11):1244-51.
  5. Qing G, Yan P, Qu Z, Liu H, Li H, and Xiao G. Hsp90 regulates processing of NF-κB2 p100 involving protection of NIK from autophagy-mediated degradation. Cell Res. 2007, 17(6): 520-30. Cover Article.
  6. Yan P, Qing G, Qu Z, Wu CC, Rabson A, and Xiao G. Targeting autophagic regulation of NF-κB in HTLV-I transformed cells by geldanamycin: implications for therapeutic interventions. Autophagy. 2007, 3(6): 600-3.
  7. Yan P, Fu J, Qu Z, Li S, Tanaka T, Grusby MJ, and Xiao G. PDLIM2 suppresses human T-cell leukemia virus type I Tax–mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation. Blood. 2009, 113(18): 4370-80.
  8. Yan P, Qu Z, Ishikawa C, Mori N, and Xiao G. Human T-cell leukemia virus type I – mediated repression of PDZ-LIM domain-containing protein 2 involves DNA methylation but independent of viral oncoprotein tax. Neoplasia. 2009, 11(10): 1036-41.
  9. Yan P*, Qu Z*, Fu J, Jiang J, Grusby MJ, Smithgall TE, and Xiao G. DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res. 2010, 70(5): 1766-72. (*Contributed equally)
  10. Qu Z, Fu J, Yan P, Hu J, Cheng SY, Xiao G. Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer. J Biol Chem. 2010, 285(16): 11786-92.
  11. Fu J, Yan P, Li S, Qu Z and Xiao G. Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis. Oncogene. 2010, 29(49): 6499-507.
  12. Fu J, Qu Z, Yan P, Ishikawa C, Ageilan RI, Rabson AB and Xiao G. The tumor suppressor gene WWOX links the canonical and non-canonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis. Blood. 2011, 117(5): 1652-61.
  13. Yan P*, Patel PD*, Seidler PM*, Patel HJ*, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Bio. 2013, 9(11):677-84. (*Contributed equally) Highlighted in AACR’s Cancer Discovery’s Research Watch, Sep. 2013; Highlighted by Nature’s SciBX: Science-Business eXchange, Oct. 2013; Highlighted by StressMarq Biosciences Inc. Science Blog, Oct. 2013
  14. Rodina A, Patel PD, Kang Y, Patel Y, Baaklini I, Wong MJ, Taldone T, Yan P, Yang C, Maharaj R, Gozman A, Patel MR, Patel HJ, Chirico W, Erdjument-Bromage H, Talele TT, Young JC, Chiosis G. Identification of an allosteric pocket on human Hsp70 reveals a mode of inhibition of this therapeutically important protein. Chem Biol (Cell press). 2013, 20(12):1469-80 Cover of the Dec. 2013 issue; Highlighted in Nature’s SciBX
  15. Rodina A, Taldone T, Kang Y, Patel PD, Koren J, Yan P, DaGama-Gomes E, Yang C, Patel MR, Shrestha L, Ochiana SO, Santarossa C, Maharaj R, Gozman A, Cox MB, Erdjument-Bromage H, Hendrickson R, Cerchietti L, Melnick A, Guzman ML, Chiosis G. Affinity purification probes of potential use to investigate the endogenous Hsp70 interactome in cancer. ACS Chemical Biology. 2014, 9(8):1698-705
  16. Patel HJ*, Patel PD*, Ochiana SO*, Yan P*, Sun W*, Patel MR*, Shah SK, Tramentozzi E, Brooks J, Boelander A, Shrestha L, Stephani RA, Finotti P, Leifer C, Li Z, Gewirth DT, Taldone T, Chiosis G. Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog, Grp94. ACS J Med Chem. 2015, 58(9):3922-43 (*Contributed equally)
  17. Rodina A*, Wang T*, Yan P*, DaGama-Gomes E*, Dunphy M*, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beettie B, Pressl C, Peter R, Xu C, Trondl R, Patel H, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq M, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz G, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson M, Lewis J, Guzman M, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016, 538:397-401 (*Contributed equally)