Tumordormancypresentsabarriertoeffectivetherapy.Tumordormancyisthoughttobecomprisedof threekeyelements:cellulardormancy,wheretumorcellsmaintainaquiescent,slow-cyclingstate,angiogenic dormancy, where the growth of the overall micro-metastasis is kept in check by apoptosis due to lack of vascularization, and immune-mediated dormancy, where the immune system continues to edit the tumor population, keeping it in equilibrium. The equilibrium of these dormant subpopulations is maintained until microenvironmental conditions favor their outgrowth. To date, it is unclear what those exact micro- environmentalconditionsare.Understandingwhytumorcellsleavethisdormantstateandbecomeaggressive isacriticalunmetneedincancerbiology.Oneindisputablefactabouttumordormancyisthatincaseswherea tumor is dormant, a significant lapse of time occurs between the diagnosis and removal of a primary tumor, andtherecurrenceofmetastasis.Duringthislapseoftime,anorganismages,andageisapoorprognostic factor for multiple tumor types, including melanoma. We hypothesize that changes in the aging microenvironment can contribute to an emergence from dormancy. Our long-term goal is to understand how theagedmicroenvironmentcontributestoanemergencefromdormancy. OurdataimplicatetheWntsignalingpathwayinmelanomadormancy.WehaveidentifiedWnt5AandsFRP2 (secretedfrizzledrelatedprotein2),astwoWntpathwaymodulatorswhoselevelandactivitywehypothesize play roles in the emergence from tumor dormancy. We have shown that aging accelerates melanoma metastasis,partlymediatedbyWnt5AandsFRP2,whichareincreasedduringaging.Ourdataindicatethat sFRP2 enhances angiogenesis, potentially regulating angiogenic dormancy. sFRP2-mediated angiogenesis has been shown to require endothelial cell expression of Wnt5A and we will test this in the context of tumor dormancy. Immune-mediated dormancy relies in part on the activity of myeloid derived suppressor cells (MDSCs),andtheirabilitytoregulateCD8+cells.OurdatashowthatMDSCsareincreasedintheagedtumor microenvironment,andfurther,thatMDSCsinthetumormicroenvironmentbegintoexpresstheirownWnt5A. Usingnovelanimalmodelswehavecreated,wewilltestthehypothesisthatnon-canonicalWntsignalingcan regulateimmune-mediateddormancyofmicrometastases,viaeffectsonangiogenesisandMDSCs.
Manyindividualsdevelopcancersthat,oncetreated,remaininremissionformany,manyyears,aprocess termed?tumordormancy?.However,afteraperiodofmanyyears,thetumorreturns,oftenasametastatic lesion,whichisveryaggressive,andnotresponsivetotherapy.Wehypothesizethatchangesthatoccurin ourbodyasweage?awaken?thesedormantcells,spurringtheirgrowthandtheiraggression.Thisproposalis designedtounderstandwhatchangesintheagingmicroenvironmentawakensdormanttumorcells.Ifwecan identifykeychangesinthisprocess,wecanbettertargetdormantcells,inordertoeradicatethemandprovide moreeffectivetherapiesforcancerpatients.
|Kugel 3rd, Curtis H; Douglass, Stephen M; Webster, Marie R et al. (2018) Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res 24:5347-5356|
|Ecker, Brett L; Kaur, Amanpreet; Douglass, Stephen M et al. (2018) Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis. Cancer Discov :|
|Kaur, Amanpreet; Ecker, Brett L; Douglass, Stephen M et al. (2018) Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov :|
|Ndoye, Abibatou; Budina-Kolomets, Anna; Kugel 3rd, Curtis H et al. (2017) ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma. Cancer Res 77:5873-5885|