Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy
Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy
批准号:
10584353
负责人:
Maria Sosa
金额:
$38.43万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2028-04-30
关键词:
AddressAgonistBar CodesBiological MarkersBiologyBone MarrowCOUP transcription factor ICancer EtiologyCancer RelapseCell Cycle ArrestCell SurvivalCessation of lifeChIP-seqChromatinClinicalClinical TrialsDataDetectionDiseaseDisease ProgressionDisease remissionDistantEndowmentEnhancersFrequenciesGenesGenetic TranscriptionGoalsGrantHead and Neck Squamous Cell CarcinomaHeterogeneityHumanIndividualKnowledgeLIF geneLungMalignant NeoplasmsMalignant neoplasm of prostateMetastatic Prostate CancerModelingMolecularMonitorNeoplasm MetastasisOrganOrgan Culture TechniquesPathway interactionsPatientsPhasePopulationPrevalencePreventionPrimary NeoplasmProliferatingProtocols documentationPublishingRecurrenceRegulationRelapseReportingRepressionResearchResidual NeoplasmRisk FactorsRoleSTAT3 geneSamplingSignal TransductionTechnologyTestingTherapeuticTimeTretinoinTumor Cell BiologyValidationWorkcancer cellcell behaviorchemotherapychromatin remodelingconventional therapydesigngain of functioninsightloss of functionlymph nodesmalignant breast neoplasmmortalityneoplastic celloncostatin Mpluripotencypredictive markerpreventprogramsresponsestem-like celltherapeutic developmenttherapy designtranscription factortranscriptome sequencingtreatment responsetumor
中文摘要
原发性肿瘤成功治疗后出现播散性肿瘤细胞(dtc)
英文摘要
Presence of disseminated tumor cells (DTCs) following successful treatment of primary
tumors poses a risk factor for metastasis which is the leading cause of cancer mortality. However, current
knowledge on mechanisms controlling the state of DTCs (persistent dormancy vs. reactivation) is limited. Only
detailed knowledge of DTC biology will open therapeutic alternatives which will extend remission.
We demonstrated that the transcription factor NR2F1/COUP-TFI triggers the dormancy phase of DTCs
in head and neck squamous cell carcinoma (HNSCC) by regulating the retinoic acid pathway and inducing a
long-lasting cell cycle arrest. Here we present new preliminary data showing that the dormant HNSCC DTC
population is heterogeneous and that the pluripotency gene SOX2 is upregulated in a subpopulation of DTCs
that co-exist with, but are distinct from, NR2F1+ dormant DTCs in the lungs and lymph nodes. SOX2 maintains
the dormancy of DTCs by upregulating LIF (leukemia inhibitory factor) and OSM (oncostatin M) signaling and by
repressing retinoic acid- and MYC-related genes. In addition, the SOX2-driven dormancy program involves
chromatin remodeling and appears to dictate a much shorter dormancy phase that facilitates higher metastasis
initiating capacity (reactivation).
We hypothesize that SOX2-induced dormancy is enabled via enhancer regulation and LIF/OSM signaling
which facilitates greater reactivation potential and metastasis-initiating capacity than the less reactivation prone
NR2F1+ DTCs. We also propose that a persistent state of dormancy with lower reactivation potential can be
induced in SOX2+ DTCs by inducing NR2F1 activity. Lastly, we propose that SOX2+ DTCs can be selectively
targeted by chemotherapy due to their higher reactivation rate. The specific aims of this study are:
SA1. To identify the mechanism of dormancy and the reactivation rate controlled by SOX2 in DTCs. We
will identify and functionalize the transcriptional targets of SOX2 (including LIF/OSM) in controlling the dormancy
and rate of reactivation by using ChIP-Seq analysis, gain and loss of function, lung-explant organ culture model,
and validation in human biospecimens.
SA2. To determine whether SOX2+ dormant DTCs can be targeted to inhibit their reactivation or
eliminated. We will determine 1- whether SOX2-driven dormancy program can be converted into an NR2F1-
driven program with low reactivation potential by using protocols to induce NR2F1 activity and 2- whether SOX2+
DTCs can be selectively targeted by chemotherapy due to their higher reactivation rate, compared to NR2F1+
DTCs by using cellular barcoding and clonal tracking technology.
Our long-term objective is to identify predictive biomarkers of the DTC status (dormant vs proliferating)
and to gain insight necessary for therapeutic strategies to either maintain DTCs in a stable dormancy phase or
induce their eradication.
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国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: