Elsa <span>R.</span> Flores, PhD
Researcher

Elsa R. Flores, PhD

Academic Rank: Senior Member

View Lab Page

Overview

The focus of my laboratory is to understand the p53 family pathway to target this pathway therapeutically in cancer.  As a basic scientist, my lab has made important discoveries in understanding the functions of the p53 family and its family members, as described below.  The overarching goal of my lab is to use this knowledge to target cancers with mutations in this pathway.  Becoming part of the Moffitt Cancer Center is essential and offers a unique opportunity to accomplish my goals.  I look forward to integrating my laboratory with others at Moffitt.

Discipline

    • Molecular Oncology
    • Cutaneous Oncology
    • Cancer Biology and Evolution Program

Education & Training

    • University of Wisconsin-Madison-McCardle Laboratory for Cancer Research, PhD - Cancer Biology
    • Massachusetts Institute of Technology, Postdoctoral Fellow
Research

The main focus of my laboratory is to understand the overlapping and unique activities of the p53 family in human cancer using mouse models and patient derived tumors.  p53 is commonly mutated in human cancer and has been difficult to target therapeutically in cancer.  This is due to the complex network of genes regulated by p53 and the extensive interactions with its family members, p63 and p73.  Prior to my work, very little was known about p63 and p73 function in cancer.  We have demonstrated that p63 and p73 are required for p53 to induce apoptosis in response to DNA damage, which is critical for the response to chemo- and radiation therapy of tumors.  Additionally, my laboratory generated genetically engineered mouse models mutant for isoforms of p63 and p73 and provided the first evidence that p63 and p73 are potent suppressors of tumorigenesis and metastasis.  Using our mouse models we have unveiled previously unappreciated functions for TAp63, which we identified as the tumor suppressive isoform of p63 in mouse and human tumors, and ∆Np63, the oncogenic isoform, in the regulation of microRNA biogenesis, stem cell maintenance, aging, and metabolism. We have also found that TAp63 and TAp73 can compensate for p53 function in vivo and found that inhibition of ∆Np63 or ∆Np73 leads to tumor regression in p53-/- mice by upregulation of TAp63 and TAp73 function and metabolic reprogramming within those tumors.  The work from my laboratory indicates that the inter-related functions of the p53 family members must be understood for effective therapy of tumors with alterations in the p53 pathway.  We are poised to make further advances in understanding the molecular mechanisms employed by this gene family in multiple biological processes.  We are currently using genomic approaches to understand the regulation of multiple downstream pathways of the p53 family including the functions and regulation of long non-coding RNAs in multiple cancers, stem cell regulation, and tumor metabolism.

Publications

  • Martin-Lopez M, Maeso-Alonso L, Fuertes-Alvarez S, Balboa D, Rodríguez-Cortez V, Weltner J, Diez-Prieto I, Davis A, Wu Y, Otonkoski T, Flores ER, Menéndez P, Marques MM, Marin MC. p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming. Cell Death Dis. 2017 Sep;8(9):e3034. Pubmedid: 28880267. Pmcid: PMC5636977.
  • Napoli M, Flores ER. Another case for diet restriction: TAp73-expressing medulloblastomas are stunted by glutamine withdrawal. Gene Dev. 2017 Sep;31(17):1715-1716. Pubmedid: 28982757. Pmcid: PMC5666670.
  • Wang S, Liang K, Hu Q, Li P, Song J, Yang Y, Yao J, Mangala LS, Li C, Yang W, Park PK, Hawke DH, Zhou J, Zhou Y, Xia W, Hung MC, Marks JR, Gallick GE, Lopez-Berestein G, Flores ER, Sood AK, Huang S, Yu D, Yang L, Lin C. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. J Clin Invest. 2017 Nov. Pubmedid: 29130936.
  • Rigoutsos I, Lee SK, Nam SY, Anfossi S, Pasculli B, Pichler M, Jing Y, Rodriguez-Aguayo C, Telonis AG, Rossi S, Ivan C, Catela Ivkovic T, Fabris L, Clark PM, Ling H, Shimizu M, Redis RS, Shah MY, Zhang X, Okugawa Y, Jung EJ, Tsirigos A, Huang L, Ferdin J, Gafà R, Spizzo R, Nicoloso MS, Paranjape AN, Shariati M, Tiron A, Yeh JJ, Teruel-Montoya R, Xiao L, Melo SA, Menter D, Jiang ZQ, Flores ER, Negrini M, Goel A, Bar-Eli M, Mani SA, Liu CG, Lopez-Berestein G, Berindan-Neagoe I, Esteller M, Kopetz S, Lanza G, Calin GA. N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration. Genome Biol. 2017 May;18(1):98. Pubmedid: 28535802. Pmcid: PMC5442648.
  • Marcet-Ortega M, Pacheco S, Martínez-Marchal A, Castillo H, Flores E, Jasin M, Keeney S, Roig I. p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes. PLoS Genet. 2017 Jun;13(6):e1006845. Pubmedid: 28617799. Pmcid: PMC5491309.
  • Napoli M, Flores ER. The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy. Brit J Cancer. 2017 Jan;116(2):149-155. Pubmedid: 27884017. Pmcid: PMC5243983.
  • Liao W, Liu H, Zhang Y, Jung JH, Chen J, Su X, Kim YC, Flores ER, Wang SM, Czarny-Ratajczak M, Li W, Zeng SX, Lu H. Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism. Sci Rep. 2017 Aug;7(1):9020. Pubmedid: 28827783. Pmcid: PMC5566403.
  • Su X, Napoli M, Abbas HA, Venkatanarayan A, Bui NH, Coarfa C, Gi YJ, Kittrell F, Gunaratne PH, Medina D, Rosen JM, Behbod F, Flores ER. TAp63 suppresses mammary tumorigenesis through regulation of the Hippo pathway. Oncogene. 2017 Apr;36(17):2377-2393. Pubmedid: 27869165. Pmcid: PMC5415945.
  • Adelmann CH, Truong KA, Liang RJ, Bansal V, Gandee L, Saporito R, Lee W, Du L, Nicholas C, Napoli M, Mino B, South AP, Proby CM, Leigh IM, Coarfa C, Flores ER, Tsai KY. MEK Is a Therapeutic and Chemopreventative Target in Squamous Cell Carcinoma. J Invest Dermatol. 2016 Sep;136(9):1920-1924. Pubmedid: 27293029. Pmcid: PMC5303342.
  • Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, Chan SM, Lodi A, Sweeney SR, Ma H, Davis RE, Baran N, Haferlach T, Su X, Flores ER, Gonzalez D, Konoplev S, Samudio I, DiNardo C, Majeti R, Schimmer AD, Li W, Wang T, Tiziani S, Konopleva M. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget. 2016 Nov;7(48):79722-79735. Pubmedid: 27806325. Pmcid: PMC5340236.
  • Napoli M, Flores ER. Unifying the p73 knockout phenotypes: TAp73 orchestrates multiciliogenesis. Gene Dev. 2016 Jun;30(11):1253-1254. Pubmedid: 27298333. Pmcid: PMC4911924.
  • Venkatanarayan A, Raulji P, Norton W, Flores ER. Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. Cell Cycle. 2016 Jan;15(2):164-171. Pubmedid: 26652033. Pmcid: PMC4825839.
  • Wang Y, Wang X, Flores ER, Yu J, Chang S. Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell. 2016 Aug;15(4):646-660. Pubmedid: 27113195. Pmcid: PMC4933665.
  • Wu Y, Lindblad JL, Garnett J, Kamber Kaya HE, Xu D, Zhao Y, Flores ER, Hardy J, Bergmann A. Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila. Cell Death Differ. 2016 Apr;23(4):723-732. Pubmedid: 26542461. Pmcid: PMC4986642.
  • Flores ER. Commentary on "Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents". Cancer Res. 2016 12;76(23):6763-6764. Pubmedid: 27909063.
  • Napoli M, Venkatanarayan A, Raulji P, Meyers BA, Norton W, Mangala LS, Sood AK, Rodriguez-Aguayo C, Lopez-Berestein G, Vin H, Duvic M, Tetzlaff MB, Curry JL, Rook AH, Abbas HA, Coarfa C, Gunaratne PH, Tsai KY, Flores ER. ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer. Cancer Cell. 2016 06;29(6):874-888. Pubmedid: 27300436. Pmcid: PMC4908836.
  • Singh MM, Johnson B, Venkatarayan A, Flores ER, Zhang J, Su X, Barton M, Lang F, Chandra J. Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neurooncol. 2015 Nov;17(11):1463-1473. Pubmedid: 25795306. Pmcid: PMC4648298.
  • Eskander MA, Ruparel S, Green DP, Chen PB, Por ED, Jeske NA, Gao X, Flores ER, Hargreaves KM. Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms. J Neurosci. 2015 Jun;35(22):8593-8603. Pubmedid: 26041925. Pmcid: PMC4452557.
  • Venkatanarayan A, Raulji P, Norton W, Chakravarti D, Coarfa C, Su X, Sandur SK, Ramirez MS, Lee J, Kingsley CV, Sananikone EF, Rajapakshe K, Naff K, Parker-Thornburg J, Bankson JA, Tsai KY, Gunaratne PH, Flores ER. IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo. Nature. 2015 Jan;517(7536):626-630. Pubmedid: 25409149. Pmcid: PMC4312210.
  • Tan EH, Morton JP, Timpson P, Tucci P, Melino G, Flores ER, Sansom OJ, Vousden KH, Muller PA. Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene. 2014 Jun;33(25):3325-3333. Pubmedid: 23873029. Pmcid: PMC4181588.
  • Chakravarti D, Su X, Cho MS, Bui NH, Coarfa C, Venkatanarayan A, Benham AL, Flores González RE, Alana J, Xiao W, Leung ML, Vin H, Chan IL, Aquino A, Müller N, Wang H, Cooney AJ, Parker-Thornburg J, Tsai KY, Gunaratne PH, Flores ER. Induced multipotency in adult keratinocytes through down-regulation of ΔNp63 or DGCR8. Proc Natl Acad Sci U S A. 2014 Feb;111(5):E572-E581. Pubmedid: 24449888. Pmcid: PMC3918754.
  • Chaluvally-Raghavan P, Zhang F, Pradeep S, Hamilton MP, Zhao X, Rupaimoole R, Moss T, Lu Y, Yu S, Pecot CV, Aure MR, Peuget S, Rodriguez-Aguayo C, Han HD, Zhang D, Venkatanarayan A, Krohn M, Kristensen VN, Gagea M, Ram P, Liu W, Lopez-Berestein G, Lorenzi PL, Børresen-Dale AL, Chin K, Gray J, Dusetti NJ, McGuire SE, Flores ER, Sood AK, Mills GB. Copy number gain of hsa-miR-569 at 3q26.2 leads to loss of TP53INP1 and aggressiveness of epithelial cancers. Cancer Cell. 2014 Dec;26(6):863-879. Pubmedid: 25490449. Pmcid: PMC4261159.
  • Botchkarev VA, Flores ER. p53/p63/p73 in the epidermis in health and disease. Cold Spring Harb Perspect Med. 2014 Aug;4(8). Pubmedid: 25085956. Pmcid: PMC4109579.
  • Vin H, Ojeda SS, Ching G, Leung ML, Chitsazzadeh V, Dwyer DW, Adelmann CH, Restrepo M, Richards KN, Stewart LR, Du L, Ferguson SB, Chakravarti D, Ehrenreiter K, Baccarini M, Ruggieri R, Curry JL, Kim KB, Ciurea AM, Duvic M, Prieto VG, Ullrich SE, Dalby KN, Flores ER, Tsai KY. BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. Elife. 2013 Nov;2:e00969. Pubmedid: 24192036. Pmcid: PMC3814616.
  • Napoli M, Flores ER. The family that eats together stays together: new p53 family transcriptional targets in autophagy. Gene Dev. 2013 May;27(9):971-974. Pubmedid: 23651851. Pmcid: PMC3656325.
  • Liao JM, Zhang Y, Liao W, Zeng SX, Su X, Flores ER, Lu H. IκB kinase β (IKKβ) inhibits p63 isoform γ (TAp63γ) transcriptional activity. J Biol Chem. 2013 Jun;288(25):18184-18193. Pubmedid: 23589370. Pmcid: PMC3689961.
  • Cancino GI, Yiu AP, Fatt MP, Dugani CB, Flores ER, Frankland PW, Josselyn SA, Miller FD, Kaplan DR. p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependent Behavior. J Neurosci. 2013 Jul;33(31):12569-12585. Pubmedid: 23904595. Pmcid: PMC3728680.
  • Su X, Chakravarti D, Flores ER. p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer. 2013 Feb;13(2):136-143. Pubmedid: 23344544. Pmcid: PMC4181578.
  • Tran MN, Choi W, Wszolek MF, Navai N, Lee IL, Nitti G, Wen S, Flores ER, Siefker-Radtke A, Czerniak B, Dinney C, Barton M, McConkey DJ. The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of MIR-205. J Biol Chem. 2013 Feb;288(5):3275-3288. Pubmedid: 23239884. Pmcid: PMC3561548.
  • Eno CO, Zhao G, Venkatanarayan A, Wang B, Flores ER, Li C. Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress. Free Radical Bio Med. 2013 Dec;65:26-37. Pubmedid: 23770082. Pmcid: PMC3816129.
  • Chari NS, Romano RA, Koster MI, Jaks V, Roop D, Flores ER, Teglund S, Sinha S, Gruber W, Aberger F, Medeiros LJ, Toftgard R, McDonnell TJ. Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis. Cell Death Differ. 2013 Aug;20(8):1080-1088. Pubmedid: 23686138. Pmcid: PMC3705600.
  • Terrinoni A, Serra V, Bruno E, Strasser A, Valente E, Flores ER, van Bokhoven H, Lu X, Knight RA, Melino G. Role of p63 and the Notch pathway in cochlea development and sensorineural deafness. Proc Natl Acad Sci U S A. 2013 Apr;110(18):7300-7305. Pubmedid: 23589895. Pmcid: PMC3645580.
  • Ahn YH, Gibbons DL, Chakravarti D, Creighton CJ, Rizvi ZH, Adams HP, Pertsemlidis A, Gregory PA, Wright JA, Goodall GJ, Flores ER, Kurie JM. ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J Clin Invest. 2012 Sep;122(9):3170-3183. Pubmedid: 22850877. Pmcid: PMC3428095.
  • Su X, Gi YJ, Chakravarti D, Chan IL, Zhang A, Xia X, Tsai KY, Flores ER. TAp63 is a master transcriptional regulator of lipid and glucose metabolism. Cell Metab. 2012 Oct;16(4):511-525. Pubmedid: 23040072. Pmcid: PMC3483083.
  • Lee DF, Su J, Ang YS, Carvajal-Vergara X, Mulero-Navarro S, Pereira CF, Gingold J, Wang HL, Zhao R, Sevilla A, Darr H, Williamson AJ, Chang B, Niu X, Aguilo F, Flores ER, Sher YP, Hung MC, Whetton AD, Gelb BD, Moore KA, Snoeck HW, Ma'ayan A, Schaniel C, Lemischka IR. Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling. Cell Stem Cell. 2012 Aug;11(2):179-194. Pubmedid: 22862944. Pmcid: PMC3413175.
  • Flores ER. p73 is critical for the persistence of memory. Cell Death Differ. 2011 Mar;18(3):381-382. Pubmedid: 21317911. Pmcid: PMC3131993.
  • Mitani Y, Li J, Weber RS, Lippman SL, Flores ER, Caulin C, El-Naggar AK. Expression and regulation of the ΔN and TAp63 isoforms in salivary gland tumorigenesis clinical and experimental findings. Am J Pathol. 2011 Jul;179(1):391-399. Pubmedid: 21703418. Pmcid: PMC3123859.
  • Flores ER, Halder G. Stem cell proliferation in the skin: alpha-catenin takes over the hippo pathway. Sci Signal. 2011 Jul;4(183):pe34. Pubmedid: 21791701.
  • Wu H, Zeinab RA, Flores ER, Leng RP. Pirh2, a ubiquitin E3 ligase, inhibits p73 transcriptional activity by promoting its ubiquitination. Mol Cancer Res. 2011 Dec;9(12):1780-1790. Pubmedid: 21994467.
  • Bornstein C, Brosh R, Molchadsky A, Madar S, Kogan-Sakin I, Goldstein I, Chakravarti D, Flores ER, Goldfinger N, Sarig R, Rotter V. SPATA18, a spermatogenesis-associated gene, is a novel transcriptional target of p53 and p63. Mol Cell Biol. 2011 Apr;31(8):1679-1689. Pubmedid: 21300779. Pmcid: PMC3126342.
  • Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010 Oct;467(7318):986-990. Pubmedid: 20962848. Pmcid: PMC3055799.
  • Cho MS, Chan IL, Flores ER. ΔNp63 transcriptionally regulates brachyury, a gene with diverse roles in limb development, tumorigenesis and metastasis. Cell Cycle. 2010 Jun;9(12):2434-2441. Pubmedid: 20519941.
  • Lin YL, Sengupta S, Gurdziel K, Bell GW, Jacks T, Flores ER. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genet. 2009 Oct;5(10):e1000680. Pubmedid: 19816568. Pmcid: PMC2752189.
  • Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER. TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell. 2009 Jul;5(1):64-75. Pubmedid: 19570515. Pmcid: PMC3418222.
  • Su X, Cho MS, Gi YJ, Ayanga BA, Sherr CJ, Flores ER. Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf. Embo J. 2009 Jul;28(13):1904-1915. Pubmedid: 19494829. Pmcid: PMC2711186.
  • Talos F, Nemajerova A, Flores ER, Petrenko O, Moll UM. p73 suppresses polyploidy and aneuploidy in the absence of functional p53. Mol Cell. 2007 Aug;27(4):647-659. Pubmedid: 17707235.
  • Flores ER, Sengupta S, Miller JB, Newman JJ, Bronson R, Crowley D, Yang A, McKeon F, Jacks T. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005 Apr;7(4):363-373. Pubmedid: 15837625.
  • Reczek EE, Flores ER, Tsay AS, Attardi LD, Jacks T. Multiple response elements and differential p53 binding control Perp expression during apoptosis. Mol Cancer Res. 2003 Dec;1(14):1048-1057. Pubmedid: 14707288.
  • de Vries A, Flores ER, Miranda B, Hsieh HM, van Oostrom CT, Sage J, Jacks T. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci U S A. 2002 Mar;99(5):2948-2953. Pubmedid: 11867759. Pmcid: PMC122453.
  • Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002 Apr;416(6880):560-564. Pubmedid: 11932750.
  • Duensing S, Duensing A, Flores ER, Do A, Lambert PF, Münger K. Centrosome abnormalities and genomic instability by episomal expression of human papillomavirus type 16 in raft cultures of human keratinocytes. J Virol. 2001 Aug;75(16):7712-7716. Pubmedid: 11462043. Pmcid: PMC115006.
  • Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature. 2000 Oct;407(6804):645-648. Pubmedid: 11034215.
  • Flores ER, Allen-Hoffmann BL, Lee D, Lambert PF. The human papillomavirus type 16 E7 oncogene is required for the productive stage of the viral life cycle. J Virol. 2000 Jul;74(14):6622-6631. Pubmedid: 10864676. Pmcid: PMC112172.
  • Flores ER, Allen-Hoffmann BL, Lee D, Sattler CA, Lambert PF. Establishment of the human papillomavirus type 16 (HPV-16) life cycle in an immortalized human foreskin keratinocyte cell line. Virology. 1999 Sep;262(2):344-354. Pubmedid: 10502513.
  • Flores ER, Lambert PF. Evidence for a switch in the mode of human papillomavirus type 16 DNA replication during the viral life cycle. J Virol. 1997 Oct;71(10):7167-7179. Pubmedid: 9311789. Pmcid: PMC192056.