Abstract

Oneofthehallmarksofcanceristhereprogrammingofmetabolismfromoxidativephosphorylationthattakes placeinmitochondriatoglycolysis,regardlessofoxygenavailability.Thisso-called?Warburgeffect?isan importantdiseasedriverandhallmarkofpooroutcome.However,itisnowclearthatthereisgreater complexityintumormetabolism,asmitochondriacontinuetoplayanimportantroleinthebioenergeticsof transformedcells,andfuelkeycancertraitsofproliferation,drugresistance,stemnessandinvasion.Work supportedbyCA78801demonstratedthatapoolofthecancergene,survivinpresentinmitochondriaoftumor cellsmaintainedoxidativephosphorylationmetabolism.Inturn,energyproducedviathispathwayenabledthe subcellularmovementofmitochondriatothecorticalcytoskeletonoftumorcells,fuelingmembrane lamellipodiadynamics,turnoveroffocaladhesioncomplexes,andsustainedphosphorylationofcellmotility kinases.Together,thisledtoheightenedtumorchemotaxis,invasionandmetastasis,invivo.Publishedinthe peer-reviewedliterature(SciSignal8:389,2015;?PNAS112:8638,2015),anddiscussedinthreeinvitedreview articles(PharmacolRev102:42,2015;?CellCycle14:20,2015;?ClinCancerRes22:540,2016),theseresults supportedamodelofspatiotemporalmitochondrialbioenergeticsasarequirementoftumorcellmotility, invasionandmetastasis.Infollow-upstudies,wehavenowfoundthatchangesinmitochondrialsizeand shape,knownasdynamics,aswellasmechanismsoforganellequalitycontrol,suchasmitophagy,are essentialregulatorsofthispathway.Specifically,conditionsthatimpairmitochondrialfusion,promote exaggeratedmitochondrialfragmentation(fission),oractivatemitophagysuppressmitochondrialtraffickingand blocktumorcellmotility.Therefore,thehypothesisthatorganelledynamicsandqualitycontrolregulate spatiotemporalmitochondrialbioenergeticsandmetastaticcompetencecanbeformulated,andwillconstitute thefocusofthepresentrevisionapplication.IncontinuitywiththeobjectivesofCA78810,thefirstspecificaim willelucidatehowmitochondrialfusionandfissionregulateorganellemovements,membrane-actindynamics andthemachineryoftumorcellmotility.ThesecondspecificaimwillfocusonParkin-dependentand? independentmitophagy,andanovelroleoftheFUNDC2moleculeasnovel?metastasissuppressors?, regulatingmitochondrialrecruitmenttothecorticalcytoskeletonandthebioenergeticsoftumorcellinvasion. Asdynamicsandqualitycontrolaretheprimaryeffectorsofmitochondrialheterogeneity,thesestudiesarean idealmatchtotheobjectiveofthePQ5Program,willconclusivelyansweritsoverarchingquestionofhowdoes mitochondrialheterogeneityinfluencetumorigenesisorprogression,anduncoveractionabletherapeutic targetstolimitdiseasedisseminationintheclinic.

Public Health Relevance

PUBLICHEALTHRELEVANCE Mostcancerdeathsareduetothedisseminationoftumorcellstodistantorgans,aconditioncalledmetastasis. Unfortunately,westillknowlittleaboutthisprocess,andthefundamentalquestionofhowtumorcellsproduce sufficientenergytomove,invadeneighboringtissuesandcolonizedistantorganshasremainedunanswered. Thestudiesproposedinthepresentapplicationwillfillthisknowledgegap,anddissecttheroleofenergy- producingmitochondriainfuelingthemotilityoftumorcells.Theresultswilladvanceourunderstandingofthe metastaticprocess,anduncovernewtherapeutictargetstolimitdiseasedisseminationincancerpatients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA078810-19S1
Application #
9305689
Study Section
Special Emphasis Panel (ZCA1-SRB-C (J2))
Program Officer
Ault, Grace S
Project Start
1998-07-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
19
Fiscal Year
2017
Total Cost
$228,000
Indirect Cost
$108,000

  Institution

Name
Wistar Institute
Department
Type
Research Institutes
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Lu, Huimin; Bowler, Nicholas; Harshyne, Larry A et al. (2018) Exosomal ?v?6 integrin is required for monocyte M2 polarization in prostate cancer. Matrix Biol 70:20-35
Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769
Altieri, Dario C (2017) Mitochondria on the move: emerging paradigms of organelle trafficking in tumour plasticity and metastasis. Br J Cancer 117:301-305
Bryant, Kelly G; Chae, Young Chan; Martinez, Rogelio L et al. (2017) A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget 8:112184-112198
Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190
Ishida, Chiaki Tsuge; Shu, Chang; Halatsch, Marc-Eric et al. (2017) Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma. Oncotarget 8:37140-37153
Altieri, Dario C (2017) AML Therapy: Wake Up the Guardian and Cut Loose the Executioners. Cancer Cell 32:719-720
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Dheekollu, Jayaraju; Malecka, Kimberly; Wiedmer, Andreas et al. (2017) Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. Oncotarget 8:7248-7264
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74

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