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Understanding and targeting prolactin signalling in human diseases

from basic science:
  • structure-function
  • tumorigenesis
to the translational research:
  • hormone-dependent tumors
Vincent Goffin
Prolactin and Growth Hormone Pathophysiology: Translational Approaches

Vincent Goffin was trained as a molecular endocrinologist. He graduated at the University of Liège (Belgium) in 1993. After his post-doctoral training at Inserm U344, Paris (Marie-Curie fellowship), he was hired by Inserm as a tenure researcher in 1996. He is currently Research Director and heads his lab since 2006. Vincent Goffin is internationally recognized as a leader in the field of the prolactin (PRL)/growth hormone (GH) protein family. His main achievements include i) translational research on the role of PRL receptor signaling in various human diseases, with particular emphasis in Oncology, ii) preclinical development of PRL receptor inhibitors (used worldwide in academic labs) based on cutting-edge structure-function studies of receptor activation. In 2012, he founded the FASEB Science Research Conference “The GH/PRL family in biology & diseases” (ongoing conference in the FASEB series). He is/has been consultant for several companies developing PRL-related compounds and Editorial Board member or Associate Editor of 9 peer-review Journals in the field of onco-endocrinology. More recently, his research focused on prostate pathophysiology leading to the discovery in mouse models of castration-resistant luminal progenitors potentially involved in both benign prostatic hyperplasia etiology and prostate cancer relapse.

Focus

Use translational approaches to identify, understand and target cellular and molecular mechanisms responsible for the progression and resistance to treatment of prostate and breast tumors (benign and cancer), with major emphasis on prolactin, calcium, iron and stem cells.

Introduction

Breast cancer is the most commonly occurring cancer in women, and prostate cancer the second most common cancer in men. Due to the increasing lifespan in western countries, cancer incidence will continue to raise in future. When diagnosed at a localized stage, breast and prostate cancers are successfully treated by focal intervention (surgery, radiotherapy), which supports routine prevention policies (e.g. PSA screening, mammography). The standard of care of more advanced stages of the diseases involves medical treatment (e.g. anti-androgen therapy, chemotherapy). Although some tumors respond well to therapy, de novo or acquired resistance to treatment is frequently observed, leading to cancer progression towards lethal metastatic stages.

Although benign breast and prostate tumors do not predispose to cancer, they alter the quality of life of patients, e.g. lower urinary tract symptoms for patients presenting with benign prostatic hyperplasia. Beyond surgery, medical treatment of benign tumors are often empirical (breast) or face exhaustion of effect (prostate).

To improve treatment efficacy, new therapies need to be developed, which requires i) to identify the cells that resist to treatment and drive tumor relapse, ii) to better understand the mechanisms they use in escape treatment, and iii) to identify new actionable targets. Our studies mainly focus on prolactin and calcium pathways, iron metabolism, oxidative stress, inflammation and stem cell biology. Our translational approach involves the use of cell lines, primary cultures (human, mouse), genetically-modified mouse models and patient samples.

Research objectives

  1. Characterize castration-tolerant prostate cell(s) by single cell transcriptomics and identify new actionable targets to prevent prostate cancer relapse (PIs: Dr Vincent GOFFIN and Dr Jacques-Emmanuel GUIDOTTI)
  2. Use in vitro models of benign prostate hyperplasia and prostate cancer to investigate the effects of drug treatments on neuroendocrine differentiation / Isolation of prostate tumoral cells from liquid biopsies (PIs: Dr Thierry CAPIOD and Pr PATERLINI-BRECHOT)
  3. Study of iron metabolism and ferroptosis in breast cancer stem cells and study of the role of autophagy in stemness-associated plasticity in breast cancer cells (FeroStem) (PIs: Drs Ahmed HAMAI and Maryam MEHRPOUR)
  4. Use animal models of benign prostatic hyperplasia to challenge drug efficacy, elucidate exhaustion of therapeutic effect and identify alternative druggable pathways (PIs: Dr Vincent GOFFIN and Pr Nicolas BARRY DELONGCHAMPS)

5 main publications

  • Pigat, N., E. Reyes-Gomez, F. Boutillon, S. Palea, N. Barry Delongchamps, E. Koch and V. Goffin (2019). "Combined Sabal and Urtica Extracts (WS®1541) Exert Anti-proliferative and Anti-inflammatory Effects in a Mouse Model of Benign Prostate Hyperplasia." Front Pharmacol 10: 311.
  • Bernichtein, S., N. Pigat, N. Barry Delongchamps, F. Boutillon, V. Verkarre, P. Camparo, E. Reyes-Gomez, A. Mejean, S. M. Oudard, E. M. Lepicard, M. Viltard, J. C. Souberbielle, G. Friedlander, T. Capiod* and V. Goffin* (2017). "Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation." Cancer Res 77: 355-365.
  • *Mai, T. T., *A. Hamai, A. Hienzsch, T. Caneque, S. Muller, J. Wicinski, O. Cabaud, C. Leroy, A. David, V. Acevedo, A. Ryo, C. Ginestier, D. Birnbaum, E. Charafe-Jauffret, P. Codogno, *M. Mehrpour and *R. Rodriguez (2017). "Salinomycin kills cancer stem cells by sequestering iron in lysosomes." Nat Chem 9(10): 1025-1033
  • Sackmann Sala, L., F. Boutillon, G. Menara, A. De Goyon-Pelard, M. Leprevost, J. Codzamanian, N. Lister, J. Pencik, A. Clark, N. Cagnard, C. Bole-Feysot, R. Moriggl, G. P. Risbridger, R. A. Taylor, L. Kenner, J. E. Guidotti and V. Goffin (2017). "A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumors." J Pathol 243: 54-64
  • Rouet, V., R. L. Bogorad, C. Kayser, K. Kessal, C. Genestie, A. Bardier, D. R. Grattan, B. Kelder, J. J. Kopchick, P. A. Kelly and V. Goffin (2010). "Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors." Proc Natl. Acad. Sci. U. S. A 107(34): 15199-15204
Last 30 publications

2020

  • Liang G, Ling Y, Mehrpour M, Saw PE, Liu Z, Tan W, Tian Z, Zhong W, Lin W, Luo Q, Lin Q, Li Q, Zhou Y, Hamai A, Codogno P, Li J, Song, E, Gong, C. Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression. Mol Cancer. 2020; 19(1):65.
  • El Hout M, Cosialls E, Mehrpour M and Hamai A. Crosstalk between autophagy and metabolic regulation of cancer stem cells. Mol Cancer. 2020; 19(1):27
  • Plante G, Bories PN, Denjean L, Pigat N, Sibony M, Goffin V and Barry Delongchamps N. TMPRSS2-Erg/AR-V7: Prognostic value of tests in urine and biopsy rince material in prostate cancer. Prog Urol. 2020; 30(3):162-171
  • 2019

  • Pigat N, Reyes-Gomez E, Boutillon F, Palea S, Barry Delongchamps N, Koch E and Goffin V. Combined Sabal and Urtica Extracts (WS® 1541) Exert Anti-proliferative and Anti-inflammatory Effects in a Mouse Model of Benign Prostate Hyperplasia. Front Pharmacol. 2019; 10:311.
  • Patil M, Belugin S, Mecklenburg J, Wangzhou A, Paige C, Barba-Escobedo PA, Boyd JT, Goffin V, Grattan D, Boehm U, Dussor G, Price TJ and Akopian AN. Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism. iScience. 2019; 20:449-465.
  • Tandon M, Coudriet GM, Criscimanna A, Socorro M, Eliliwi M, Singhi AD, Cruz-Monserrate Z, Bailey P, Lotze MT, Zeh H, Hu J, Goffin V, Gittes GK, Biankin AV and Esni F. Prolactin Promotes Fibrosis and Pancreatic Cancer Progression. Cancer Res. 2019; 79(20):5316-5327.
  • Boutillon F, Pigat N, Sala LS, Reyes-Gomez E, Moriggl R, Guidotti JE and Goffin V. STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice. Cancers (Basel). 2019; 11(7). pii: E929
  • Olmos-Ortiz A, Deciga-Garcia M, Preciado-Martinez E, Bermejo-Martinez L, Flores-Espinosa P, Mancilla-Herrera I, Irles C, Helguera-Repetto AC, Quesada-Reyna B, Goffin V, Diaz L and Zaga-Clavellina V. Prolactin decreases LPS-induced inflammatory cytokines by inhibiting TLR-4/NFkappaB signaling in the human placenta. Mol Hum Reprod. 2019. 25(10):660-667
  • Patil M, Hovhannisyan AH, Wangzhou A, Mecklenburg J, Koek W, Goffin V, Grattan D, Boehm U, Dussor G, Price TJ and Akopian AN. Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent. J Neuroendocrinol. 2019; 31(8):e12759.
  • Goncalves TJM, Boutillon F, Lefebvre S, Goffin V, Iwatsubo T, Wakabayashi T, Oury F and Armand AS. Collagen XXV promotes myoblast fusion during myogenic differentiation and muscle formation. Sci Rep. 2019; 9(1):5878.
  • de Dios N, Orrillo S, Irizarri M, Theas MS, Boutillon F, Candolfi M, Seilicovich A, Goffin V, Pisera D and Ferraris J. JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes. Neuroendocrinology. 2019; 108(2):84-97.
  • Asad AS, Nicola Candia AJ, Gonzalez N, Zuccato CF, Abt A, Orrillo SJ, Lastra Y, De Simone E, Boutillon F, Goffin V, Seilicovich A, Pisera DA, Ferraris MJ and Candolfi M. Prolactin and its receptor as therapeutic targets in glioblastoma multiforme. Sci Rep. 2019; 9(1):19578.
  • Anract J, Baures M, Barry Delongchamps N, Capiod T. Microcalcifications, calcium-sensing receptor, and cancer. Cell Calcium 2019; 82:102051
  • Yannoutsos A, Fontaine M, Galloula A, Damotte D, Chatellier G, Paterlini-Brechot P, Meyer G, Pastre J, Duchatelle V, Marini V, Schwering KL, Lazareth I, Ghaffari P, Stansal A, Sanson H, Labrousse C, Beaussier H, Nasr NB, Zins M, Salmeron S, Messas E, Lajonchere JP, Emmerich J, Priollet P, Tredaniel J. Peripheral arterial disease and systematic detection of circulating tumor cells: rationale and design of the DETECTOR prospective cohort study. BMC Cardiovasc Disord 2019; 19:212
  • Broncy L, Paterlini-Brechot P. Clinical Impact of Circulating Tumor Cells in Patients with Localized Prostate Cancer. Cells 2019; 8(7). pii: E676.
  • 2018

  • Capiod T, Barry Delongchamps N, Pigat N, Souberbielle JC, Goffin V. Do dietary calcium and vitamin D matter in men with prostate cancer? Nat Rev Urol 2018; 15:453-461
  • Karayazi Atici O, Urbanska A, Gopinathan SG, Boutillon F, Goffin V, Shemanko CS. ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage. Endocrinology 2018; 159:907-930
  • Jallow F, Brockman JL, Helzer KT, Rugowski DE, Goffin V, Alarid ET, Schuler LA. 17beta-Estradiol and ICI182,780 Differentially Regulate STAT5 Isoforms in Female Mammary Epithelium, With Distinct Outcomes. J Endocr Soc 2018; 2:293-309
  • Shea MP, O'Leary KA, Fakhraldeen SA, Goffin V, Friedl A, Wisinski KB, Alexander CM, Schuler LA. Antiestrogen Therapy Increases Plasticity and Cancer Stemness of Prolactin-Induced ERalpha(+) Mammary Carcinomas. Cancer Res 2018; 78:1672-1684
  • Oclon E, Solomon G, Hayouka Z, Salame TM, Goffin V, Gertler A. Novel reagents for human prolactin research: large-scale preparation and characterization of prolactin receptor extracellular domain, non-pegylated and pegylated prolactin and prolactin receptor antagonist. Protein Eng Des Sel 2018; 31:7-16
  • El Hout M, Dos Santos L, Hamai A, Mehrpour M. A promising new approach to cancer therapy: Targeting iron metabolism in cancer stem cells. Semin Cancer Biol 2018; 53:125-138
  • Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD, Hoshyar R, Seyfoori A, Sepehri Z, Ande SR, Khadem F, Akbari M, Gorman AM, Samali A, Klonisch T, Ghavami S. Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 2018; 184:13-41
  • Broncy L, Paterlini-Brechot P. Circulating Tumor Cells for the Management of Renal Cell Carcinoma. Diagnostics (Basel) 2018; 8, 63 doi:10.3390/diagnostics8030063
  • Broncy L, Njima BB, Mejean A, Beroud C, Romdhane KB, Ilie M, Hofman V, Muret J, Hofman P, Bouhamed HC, Paterlini-Brechot AP. Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma. Oncotarget 2018; 9:20058-20074
  • Braun AC, de Mello CAL, Corassa M, Abdallah EA, Urvanegia AC, Alves VS, Flores B, Diaz M, Nicolau UR, Silva VSE, Calsavara V, Paterlini-Brechot P, Chinen LTD. EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas. Cancer Biol Ther 2018; 19:454-460
  • 2017

  • Bernichtein S, Pigat N, Barry Delongchamps N, Boutillon F, Verkarre V, Camparo P, Reyes-Gomez E, Mejean A, Oudard SM, Lepicard EM, Viltard M, Souberbielle JC, Friedlander G, Capiod T, Goffin V. Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation. Cancer Res 2017; 77:355-365
  • Castillo LF, Rivero EM, Goffin V, Luthy IA. Alpha2-adrenoceptor agonists trigger prolactin signaling in breast cancer cells. Cell Signal 2017; 34:76-85
  • Sackmann Sala L, Boutillon F, Menara G, De Goyon-Pelard A, Leprevost M, Codzamanian J, Lister N, Pencik J, Clark A, Cagnard N, Bole-Feysot C, Moriggl R, Risbridger GP, Taylor RA, Kenner L, Guidotti JE, Goffin V. A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumors. J Pathol 2017; 243:54-64
  • Goffin V. Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol Ther 2017; 179:111-126
  • Mai TT, Hamai A, Hienzsch A, Caneque T, Muller S, Wicinski J, Cabaud O, Leroy C, David A, Acevedo V, Ryo A, Ginestier C, Birnbaum D, Charafe-Jauffret E, Codogno P, Mehrpour M, Rodriguez R. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem 2017; 9:1025-1033
  • Hamai A, Caneque T, Muller S, Mai TT, Hienzsch A, Ginestier C, Charafe-Jauffret E, Codogno P, Mehrpour M, Rodriguez R. An iron hand over cancer stem cells. Autophagy 2017; 13:1465-1466
  • Hamai A, Mehrpour M. [Autophagy and iron homeostasis]. Med Sci (Paris) 2017; 33:260-267
  • Laget S, Broncy L, Hormigos K, Dhingra DM, BenMohamed F, Capiod T, Osteras M, Farinelli L, Jackson S, Paterlini-Brechot P. Technical Insights into Highly Sensitive Isolation and Molecular Characterization of Fixed and Live Circulating Tumor Cells for Early Detection of Tumor Invasion. PLoS One 2017; 12:e0169427
  • Del Prete D, Suski JM, Oules B, Debayle D, Gay AS, Lacas-Gervais S, Bussiere R, Bauer C, Pinton P, Paterlini-Brechot P, Wieckowski MR, Checler F, Chami M. Localization and Processing of the Amyloid-beta Protein Precursor in Mitochondria-Associated Membranes. J Alzheimers Dis 2017; 55:1549-1570
  • Maschalidi S, Nunes-Hasler P, Nascimento CR, Sallent I, Lannoy V, Garfa-Traore M, Cagnard N, Sepulveda FE, Vargas P, Lennon-Dumenil AM, van Endert P, Capiod T, Demaurex N, Darrasse-Jeze G and Manoury B. UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells. Nat Commun. 2017; 8(1):1640
  • 2016

  • Sutherland A, Forsyth A, Cong Y, Grant L, Juan TH, Lee JK, Klimowicz A, Petrillo SK, Hu J, Chan A, Boutillon F, Goffin V, Egan C, Tang PA, Cai L, Morris D, Magliocco A, Shemanko CS. The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation. J Natl Cancer Inst 2016; 108
  • Chakhtoura Z, Laki F, Bernadet M, Cherifi I, Chiche A, Pigat N, Bernichtein S, Courtillot C, Boutillon F, Bieche I, Vacher S, Tanguy ML, Bissery A, Grouthier V, Camparo P, Foretz M, Do Cruzeiro M, Pierre R, Rakotozafy F, Tichet J, Tejedor I, Guidotti JE, Sigal-Zafrani B, Goffin V, Touraine P. Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk. J Clin Endocrinol Metab 2016; 101:4449-4460
  • Gaston J, Cheradame L, Yvonnet V, Deas O, Poupon MF, Judde JG, Cairo S, Goffin V. Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents. Oncotarget 2016; 7:77205-77224
  • Tang MW, Reedquist KA, Garcia S, Fernandez BM, Codullo V, Vieira-Sousa E, Goffin V, Reuwer AQ, Twickler MT, Gerlag DM, Tak PP. The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation. Rheumatology (Oxford) 2016
  • Melendez Garcia R, Arredondo Zamarripa D, Arnold E, Ruiz-Herrera X, Noguez Imm R, Baeza Cruz G, Adan N, Binart N, Riesgo-Escovar J, Goffin V, Ordaz B, Pena-Ortega F, Martinez-Torres A, Clapp C, Thebault S. Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death. EBioMedicine 2016; 7:35-49
  • Orhon I, Dupont N, Zaidan M, Boitez V, Burtin M, Schmitt A, Capiod T, Viau A, Beau I, Kuehn EW, Friedlander G, Terzi F and Codogno P. Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat Cell Biol. 2016; 18(6):657-667
  • Capiod T. Extracellular Calcium Has Multiple Targets to Control Cell Proliferation. Adv Exp Med Biol. 2016; 898:133-56.
  • Permanent researcher
    Nicolas Barry Delongchamps
    Professor Researcher
    +33 (0)1 58 41 27 83
    Thierry Capiod
    Researcher
    +33 (0)1 40 61 53 25
    Vincent Goffin
    Researcher
    +33 (0)1 40 61 53 23
    Jacques-Emmanuel Guidotti
    Researcher
    +33 (0)1 40 61 53 27
    Ahmed Hamai
    Researcher
    +33 (0)1 40 61 53 29
    Maryam Mehrpour
    Researcher
    +33 (0)1 40 61 53 28
    Patrizia Paterlini-Brechot
    Professor Researcher
    +33 (0)1 40 61 53 26
    Michael Peyromaure-Debord-Broca
    Professor Researcher
    Philippe Touraine
    Professor Researcher
    +33 (0)1 42 16 02 54
    Permanent engineer
    Emeline Pacreau
    -
    Natascha Pigat
    -
    +33 (0)1 40 61 53 24
    PhD
    Manon Baures
    PhD Student
    Emma Cosialls
    PhD Student
    Leila Dos Santos
    PhD Student
    Laura Garrido Castillo
    PhD Student
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    Support(s)
    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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