Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
基本信息
- 批准号:10517874
- 负责人:
- 金额:$ 97.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-21 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:CarcinomaCell CommunicationCell DeathCellsClinicClinicalClinical ResearchCoculture TechniquesCollagenCollagen FiberCollagen ReceptorsCollagen Type IComplexDDR1 geneDataDepositionDesmoplasticEnvironmentEquilibriumExcisionExtracellular MatrixExtracellular Matrix ProteinsFailureFiberFibroblastsGoalsGrowthHumanImmuneImmune checkpoint inhibitorImmunityImmunologic SurveillanceImmunosuppressionInfiltrationLengthLigandsLiverMalignant - descriptorMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of liverMalignant neoplasm of pancreasMediatingMediator of activation proteinMetabolicMetabolismMetastatic Neoplasm to the LiverMusNeoplasm MetastasisNutrientPancreatic Ductal AdenocarcinomaPatientsProgression-Free SurvivalsReceptor SignalingRegulationResearchResistanceResolutionRoleSignal PathwaySignal TransductionSiteSliceSpecimenStarvationTestingTherapeutic InterventionTimeTumor ImmunityTumor PromotionTumor SuppressionTumor-infiltrating immune cellsVascular blood supplyVisceral metastasisantitumor effectbaseimmune activationimmune checkpoint blockadeimmune clearanceimprovedindexingindividualized medicinemouse modelnovelnovel strategiesnovel therapeuticspancreatic ductal adenocarcinoma cellrational designreceptorrefractory cancersingle-cell RNA sequencingtargeted treatmenttherapy developmenttherapy resistanttooltraittranscriptomicstranslational scientisttumortumor growthtumor metabolism
项目摘要
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic and therapy-resistant cancer. The role of
the desmoplastic stroma in PDAC remains elusive with studies supporting both tumor-promoting or tumor-
restricting functions. The failure of stroma targeting therapies suggests that a deeper understanding of the
complex cancer-stroma interaction is needed. Type I collagen (Col I), the major ECM protein in PDAC, can
physically restrain tumors and limit nutrient availability. Yet, PDAC cells adapt and exploit the surrounding stroma
to acquire more advanced malignant traits. Moreover, the desmoplastic collagen-rich stroma may suppress
immunosurveillance and activate tumor-promoting mechanosensitive signaling. It is likely that tumor-promoting
and tumor-suppressive effects of CAF and ECM occur in parallel and that their balance determines the net effect
on PDAC growth. We seek to better understand these opposing functions by focusing on Col I as a key mediator
of stroma-PDAC crosstalk. Clinical studies show improved progression-free survival (PFS) after resection in
patients with “inert stroma” characterized by extensive ECM deposition and low fibrolytic activity, whereas highly
fibrolytic stroma is associated with much shorter PFS times. Based on this finding we hypothesize that rather
than the sheer quantity of CAF and stroma, collagen fibrolysis and differential effects of receptors that
discriminate between intact and cleaved Col I dictate tumor growth and immunity. Our preliminary data support
this hypothesis, indicating differential regulation of cancer cell metabolism by intact and cleaved collagen through
a specific receptor, DDR1; as well as high expression of the inhibitory Col I receptor LAIR1 on immune cells and
a role for Col I in immune cell infiltration and activation in PDAC spread to the liver, the most common site of
metastasis and a suppressor of systemic anti-tumor immunity. Our long-term goal is to develop therapies that
target collagen receptors and shift the balance from immunosuppression and tumor promotion by cleaved
collagen to tumor starvation, growth inhibition and enhanced anti-tumor immunity, rather than CAF depletion or
modulation, which so far had resulted in untoward effects. Our interdisciplinary team of basic and clinical-
translational investigators will utilize clinical specimens, tumor slice cultures, single cell RNA-sequencing, spatial
transcriptomics, mouse models and PDAC-ECM co-cultures to elucidate the role of collagen receptor signaling
via two closely integrated specific aims: 1. Test the hypothesis that collagen fragments and fibers antagonistically
control PDAC metabolism through the PDAC-intrinsic collagen receptor DDR1, whose inhibition can switch off
tumor metabolism and induce cell death. 2. Test the hypothesis that stimulatory and inhibitory collagen receptors
control anti-PDAC immunity and can be combined with immune checkpoint inhibitors to increase anti-tumor
immunity. The successful completion of these research goals will provide us with novel tools for converting
stroma-mediated tumor growth and immunosuppression to growth inhibition and anti-tumor immunity.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michael Karin其他文献
Michael Karin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michael Karin', 18)}}的其他基金
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
- 批准号:
10516935 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy
研究肝内胆管癌发病机制和免疫生物学并改进其免疫治疗的新小鼠模型
- 批准号:
10711615 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
- 批准号:
10708168 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
- 批准号:
10503841 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
- 批准号:
10670920 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments.
癌细胞产生的胶原蛋白 1 同源三聚体对微环境胶原蛋白 1 片段激活 DDR1 信号传导的影响。
- 批准号:
10831212 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
- 批准号:
10182897 - 财政年份:2020
- 资助金额:
$ 97.11万 - 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
- 批准号:
10266224 - 财政年份:2020
- 资助金额:
$ 97.11万 - 项目类别:
Control of Lipogenesis and Hepatic Steatosis by Caspase-2
Caspase-2 对脂肪生成和肝脂肪变性的控制
- 批准号:
10322660 - 财政年份:2019
- 资助金额:
$ 97.11万 - 项目类别:
Control of Lipogenesis and Hepatic Steatosis by Caspase-2
Caspase-2 对脂肪生成和肝脂肪变性的控制
- 批准号:
10083211 - 财政年份:2019
- 资助金额:
$ 97.11万 - 项目类别:
相似海外基金
Cell-cell communicationから紐解く、心臓前駆細胞を取り巻く細胞社会の解明
通过细胞间通讯阐明心脏祖细胞周围的细胞社会
- 批准号:
24K02429 - 财政年份:2024
- 资助金额:
$ 97.11万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Understanding MMP3-rich exosomes on neoplastic cell communication in tumor microenvironment
了解富含 MMP3 的外泌体对肿瘤微环境中肿瘤细胞通讯的影响
- 批准号:
22KF0268 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Otganotypic vascular patterning regulated by cell-to-cell communication
细胞间通讯调节的基因型血管模式
- 批准号:
23H02661 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Control of Intestinal Epithelial Function through Lymphatic-Intestinal Stem Cell Communication
通过淋巴-肠干细胞通讯控制肠上皮功能
- 批准号:
10591264 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
Control of Intestinal Epithelial Function through Lymphatic-Intestinal Stem Cell Communication
通过淋巴-肠干细胞通讯控制肠上皮功能
- 批准号:
10924377 - 财政年份:2023
- 资助金额:
$ 97.11万 - 项目类别:
Delayed wound healing in diabetic corneal epithelia: reduction in protein response after injury and uncoordinated cell-cell communication
糖尿病角膜上皮伤口愈合延迟:损伤后蛋白质反应减少和细胞间通讯不协调
- 批准号:
10387681 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
CXCR3-Mediated Cell-Cell Communication in Glaucoma
CXCR3 介导的青光眼细胞间通讯
- 批准号:
10684834 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
Delayed wound healing in diabetic corneal epithelia: reduction in protein response after injury and uncoordinated cell-cell communication
糖尿病角膜上皮伤口愈合延迟:损伤后蛋白质反应减少和细胞间通讯不协调
- 批准号:
10663786 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
Extracellular vesicles as mediators of cell-cell communication during implantation
细胞外囊泡作为植入过程中细胞间通讯的介质
- 批准号:
10684030 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:
CXCR3-Mediated Cell-Cell Communication in Glaucoma
CXCR3 介导的青光眼细胞间通讯
- 批准号:
10539828 - 财政年份:2022
- 资助金额:
$ 97.11万 - 项目类别:














{{item.name}}会员




