Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis
癌细胞-肿瘤发生的外在和内在调节因子
基本信息
- 批准号:10282401
- 负责人:
- 金额:$ 21.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-02 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectAntibodiesBehaviorBindingBiochemicalCRISPR screenCancer cell lineCarcinomaCell LineCellsCessation of lifeCommunicationDataDermalDevelopmentExhibitsFibroblastsFibronectinsGenesGeneticHeterogeneityHistologicHumanImmuneInstitutionIntegrinsIntrinsic factorKnock-outKnowledgeLeadLigandsLinkMalignant - descriptorMalignant NeoplasmsMediatingMentorshipMinorityModelingMolecularMorbidity - disease rateMultiplexed Ion Beam ImagingNeoplasmsNeoplastic KeratinocyteOncogenicOrganoidsPathway interactionsPatientsPhysiciansPre-Clinical ModelProcessPrognosisRecurrenceResearchRiskRoleScientistSignal TransductionSiteSkinSkin CancerStromal CellsStromal InvasionSuggestionTherapeuticTumor Cell InvasionTumor-DerivedUnited StatesUniversitiesUnresectableUp-RegulationWorkXenograft procedurecancer cellcancer geneticscancer typecell typecohortconnective tissue growth factorgenetic manipulationgenetic signaturein vivokeratinocytemouse modelmutantneoplastic cellnovelnovel therapeutic interventionpreventreceptorsingle-cell RNA sequencingskin squamous cell carcinomatranscriptomicstreatment strategytumortumor growthtumor heterogeneitytumor microenvironmenttumor progressiontumorigenesistumorigenic
项目摘要
PROJECT SUMMARY/ABSTRACT
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer overall in the U.S. and
causes substantial morbidity, with a significant risk of metastatic spread and death. Treatment options are limited
in unresectable cases, which are estimated at up to 40,000 per year. Advances in treatment have been hindered
by incomplete knowledge of intratumoral heterogeneity (ITH) in cSCC, particularly regarding how different tumor
subpopulations behave within a growing tumor. ITH can be driven by cell-intrinsic abnormalities within cancer
cells, but increasing evidence suggests that cancer cells communicate with diverse cell types, such as immune
or stromal cells, in the tumor microenvironment (TME) to coordinate malignant behavior such as invasion. Thus,
a deeper understanding of how ITH arises in cSCC, from both TME and cell-intrinsic contributions, has the
potential to yield new treatment strategies.
Recent discovery of a novel subpopulation of cSCC tumor cells was facilitated through single-cell profiling of
patient cSCC tumors. This tumor-specific keratinocyte (TSK) subpopulation was found to express a gene
signature that was absent in normal skin, suggestive of invasive capacity, and associated with worse prognosis
across several epithelial cancers. Spatial profiling demonstrated that TSKs resided at the tumor leading edge
adjacent to cancer-associated fibroblasts (CAFs), suggesting that crosstalk among these cell types in the TME
may control TSK cell state or function. Global ligand-receptor analyses integrating single-cell and spatial data
nominated specific CAF-derived ligands matched with receptors expressed by TSKs, including several integrins.
Integrin signaling genes mediating TME signals were required for tumor growth in CRISPR screens in vivo,
including ITGB1, FERMT1, CD151, and ARPC2. Thus, these data support a model in which signals derived from
TME cells proximal to TSKs promote tumorigenesis and potential invasion through ITGB1-mediated signaling.
Through two specific aims, this work will determine if blocking cSCC-specific CAF-derived factors and
disabling cancer subpopulation-intrinsic factors can impede TSK formation and subsequent tumor invasion and
progression in preclinical models. Aim I will employ a human organoid model of cSCC to assess the contribution
of CAF-derived ligands toward emergence of TSKs and invasion through genetic ablation and therapeutic
blockade. Aim II will determine how TSK subpopulation-specific factors cooperate to facilitate invasion in
organoids and tumorigenesis in xenograft mouse models through genetic manipulation of cancer cells to prevent
factor interaction. This work will be performed under the mentorship of Dr. Paul Khavari, a physician-scientist
and expert in skin cancer genetics, at Stanford University, a world-class research institution. These studies could
aid the development of novel therapeutic strategies to treat unresectable cSCC and lead to a deeper molecular
understanding of pathways enabling tumor invasion, heterogeneity, and progression.
项目总结/文摘
项目成果
期刊论文数量(0)
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Andrew Ji其他文献
Andrew Ji的其他文献
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{{ truncateString('Andrew Ji', 18)}}的其他基金
Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis
癌细胞-肿瘤发生的外在和内在调节因子
- 批准号:
10682445 - 财政年份:2021
- 资助金额:
$ 21.7万 - 项目类别:
Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis
癌细胞-肿瘤发生的外在和内在调节因子
- 批准号:
10480068 - 财政年份:2021
- 资助金额:
$ 21.7万 - 项目类别:
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