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SUMMARY:Metastasis latency: new molecular insights - Roger Gomis\, ICREA R
 esearch Professor\, IRB Barcelona
DTSTART:20171107T113000Z
DTEND:20171107T123000Z
UID:TALK93871@talks.cam.ac.uk
CONTACT:Mala Jayasundera
DESCRIPTION:_Roger R. Gomis_\n\n_Oncology Program\, Institute for Research
  in Biomedicine (IRB Barcelona)\, The Barcelona Institute of Science and T
 echnology\, Barcelona\, Spain and ICREA\, Institució Catalana de Recerca 
 i Estudis Avançats\, Barcelona\, Spain_ \n\nAlthough breast cancer (BCa) 
 can relapse to bones\, lungs and liver as well as brain\, metastasis frequ
 ently becomes prevalent in one organ long before it does in others\, and b
 rain metastasis tends to be a late event. The ability to metastasize to a 
 secondary site can be stochastic\, owing to new interactions between the t
 umor cell and the target microenvironment\, or can be encoded by the arriv
 ing tumor cell. The slow progression of certain subtypes of BC under these
  different selective conditions gives rise to metastatic speciation\, as s
 uggested by the different kinetics of BC relapse to different sites in the
  same patient\, and by the coexistence of malignant cells with different o
 rgan tropisms in patient-derived samples. We aimed to set the stage for th
 e detailed study of the mechanisms of metastasis and their potential value
  as therapeutic targets.\n\nFor many BCa patients\, symptomatic bone metas
 tases appear after years or even decades of latency. How metastatic cells 
 disseminate\, and how micrometmastatic lesions remain dormant and undetect
 able yet initiate colonization\, are major questions in cancer research. W
 e identify and functionally analyse a molecular mechanism involved in bone
  metastatic latency of estrogen receptor–positive (ER)＋ BCa. We develo
 ped an in vivo loss-of-function\, genome-wide shRNA screening to identify 
 genes relevant for long-latent relapse in BCa. This screen revealed an imp
 ortant regulator of metastatic dormancy. Notably\, low expression associat
 es with early metastasis in ER+ BCa patients and reduced levels impaired c
 ellular differentiation of metastatic cells. These effects are mediated th
 rough modulation of chromatin status at promoters to regulate the expressi
 on of luminal differentiation genes\, which prevent the progression of ER+
  BCa towards metastasis. Our results identify the regulation of luminal ce
 ll differentiation via modulation of chromatin remodelling to be a key mec
 hanism for controlling metastatic dormancy in BCa. \n\nRecently\, we have 
 also examined the mechanisms that allow prostate and BCa cells to metaboli
 cally sustain rapid growth in the primary and distant sites. Cellular tran
 sformation and cancer progression is accompanied by changes in the metabol
 ic landscape. Cancer genes (oncogenes and tumor suppressors) maintain the 
 metabolic homeostasis when functional\, and alterations in these genes pro
 mote an imbalance in the metabolic homeostasis and induce the metabolic sw
 itch. The metabolic switch in cancer encompasses a plethora of discrete en
 zymatic activities that must be coordinately altered to ensure the generat
 ion of biomass\, reductive power and the remodeling of the microenvironmen
 t. In BCa\, we reveal that FoxA factors provide a central metabolic growth
  function by specifically regulating LIPG expression\, thereby allowing th
 e acquisition of indispensable extracellular lipids for tumor proliferatio
 n\, whereas in prostate cancer\, PGC1α acts a master regulator of metabol
 ism that opposes the dissemination of the disease.
LOCATION:Sackler Lecture Theatre (Level 7)\, Cambridge Institute for Medic
 al Research
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