?Project1 Our previous data have shown that the aged microenvironment drives resistance to targeted therapy, and may impact response to immunotherapyas well. Tumor cells undergo metabolic reprogramming in order to acquire resistance to BRAF/MEK inhibitors. We have found that one of the contributing factors to this resistance may be lipids. Aged or stressed fibroblasts secrete lipids, whichare takenup by melanoma cells, promoting their ability to invade, and resist targeted therapy. These stromally-induced changes can also affect immune cells. Dendritic cells (DC) are required for the initiation and maintenance of immune responses and lipid accumulation in DC decreases their ability to act as antigen presenting cells. Myeloid derivedsuppressorcells(MDSCs)playamajorroleinregulationofantitumorimmunity.Thesecellsthriveon lipidmetabolismandtheyaccumulateanduseoxidizedlipidstoaugmenttheirabilitytosuppresstheimmune microenvironment.Wehaveimplicatedfattyacid(FA)transporterprotein2(FATP2)inlipidaccumulationby bothtumorcellsandPMN-MDSC,suggestingacomplexcrosstalkbetweenmultiplecomponentsoftheTME. We propose to identify the mechanism and subsequent functional consequences of lipid accumulation in tumorcellsandMDSCs. WewillevaluatetheeffectoftherapeutictargetingoflipidaccumulationinMDSCs on the generation of immune responses in melanoma models, and on tumor cell fate and response to targetedtherapy.
?Project1 The prognosis for melanoma patients over the age of 60 is markedly lower than younger patients, and therapy is less effective. We have discovered that aged fibroblasts secrete lipids that affect melanoma cell response to therapy, as well as the activity of myeloid derived suppressor cells. In this project, we will elucidate the mechanisms by which this occurs, and determine the implications of lipid accumulation in the agedtumormicroenvironmentfortherapyofmelanoma.
|Emptage, Ryan P; Lemmon, Mark A; Ferguson, Kathryn M et al. (2018) Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 26:1137-1143.e3|
|Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705|
|Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426|
|Pathria, Gaurav; Scott, David A; Feng, Yongmei et al. (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J 37:|
|Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072|
|Rebecca, Vito W; Nicastri, Michael C; Fennelly, Colin et al. (2018) PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. 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 :|
|Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386|
|Ojha, Rani; Leli, Nektaria M; Onorati, Angelique et al. (2018) ER translocation of the MAPK pathway drives therapy resistance in BRAF mutant melanoma. Cancer Discov :|
|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|
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