Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
基本信息
- 批准号:10683305
- 负责人:
- 金额:$ 50.35万
- 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:2022-08-12 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcetylgalactosamineAffectAntigensAppearanceApplications GrantsBindingCD44 geneCRISPR/Cas technologyCancer EtiologyCarbohydratesCessation of lifeClinicalCo-ImmunoprecipitationsDataDiseaseDisease ProgressionDistantDistant MetastasisGalactoseGalactosyltransferasesGlycobiologyGlycopeptidesGlycoproteinsGoalsHistocytochemistryHumanIncidenceKPC modelKRASG12DKnock-outLectinLiverLungMalignant NeoplasmsMalignant neoplasm of pancreasMass Spectrum AnalysisMediatingMembraneModelingMolecularMolecular WeightMucin 1 proteinMucinsMusMutationNeoplasm MetastasisNormal CellNormal tissue morphologyO-Glycans Biosynthesis PathwayOncogenicOrganOrganoidsPathway interactionsPeptidesPeritoneumPlayPolysaccharidesQuantitative EvaluationsRoleSamplingSeverity of illnessStructureTP53 geneTestingTherapeuticTissuesTranslatingTumorigenicityVaccinesVariantVertebral columncancer stem cellcarbohydrate structureclinical diagnosisclinically significantdesignearly onsetglycosylationglycosyltransferaseimprovedin vivoinsightlymph nodesmortalitymouse modelnovel therapeutic interventionnovel therapeuticspancreatic cancer cellspancreatic cancer patientspreventsialylationstem cell biomarkersstemnesssuccesssugartranscriptome sequencingtumor progressiontumorigenesis
项目摘要
Pancreatic cancer (PC) is the fourth leading cause of cancer death and often goes undiagnosed until it has already
advanced and metastasized. Aberrant changes in O-glycans, such as increased expression of truncated
carbohydrate antigens (Tn, sialylated Tn/STn), are commonly observed in PC. However, the mechanistic
involvement of these truncated O-glycan structures in PC progression and metastasis is under-explored. Hence,
our study is focused on investigating the mechanistic role of truncated O-glycans during early metastatic
dissemination in PC. The O-glycosyltransferase Core 1 β1,3-Galactosyltransferase (C1GALT1) catalyzes the
second step of mucin-type O-glycan biosynthesis by adding galactose to the first sugar N-acetylgalactosamine
(Tn) that forms the Core 1 carbohydrate structure. Such structures are usually elongated to mature O-glycans
found on normal tissue, but their extension may be truncated at the Tn-glycan stage during cancer due to inactive
C1GALT1 activity. Our preliminary data demonstrated the loss of O-glycosyltransferase activity, C1GALT1, in a
subset of (poorly differentiated) human PC tissue. Further, CRISPR/Cas9-based C1GALT1 knockout (KO) in PC
cells resulted in aberrant O-glycosylation (increased Tn and STn glycans). Along with glycan alterations presented
upon oncogenic glycoproteins (mucin glycoproteins and cancer stem cell markers), our studies also indicate
increased tumorigenicity and metastasis of C1GALT1 KO PC cells. We have also observed O-glycan truncation
present on CD44, a cancer stem cell marker, in C1GALT1 models. Interestingly, knockout of C1galt1 along with
KrasG12D and Trp53R172H/+ mutations in mouse models resulted in early-onset (in 3 weeks) and early distant
metastasis (in 10 weeks) of PC. Based on these observations, our major goal is to investigate the mechanistic
role of truncated O-glycans in PC progression and metastasis. Based on these observations, we hypothesize
that "Truncated O-glycans on cancer-associated glycoproteins (mucins and stemness markers) induce the early
onset of progression and metastatic dissemination in pancreatic cancer." To test this hypothesis, the following
aims are proposed. The first aim will investigate the functional impact of C1GALT1 expression and aberrant
glycosylation profile on cancer-associated glycoproteins in pancreatic cancer. The second aim will elucidate how
truncated O-glycans (such as Tn and STn) on membrane-bound mucins and stemness markers facilitate
pancreatic cancer metastasis. The third aim will determine, in vivo, the impact of truncated O-glycans in the early
onset of pancreatic cancer metastasis using C1galt1 knockout KC and KPC mice. The proposed studies will
establish the association of aberrant expression of truncated Tn and STn glycans with differential membrane-
bound mucin function during PC progression and metastasis. This study will significantly contribute to our
knowledge of mucin glycobiology in cancer. Altogether, this proposed study will also pave the way for developing
novel therapeutics for modulating membrane-bound mucin function in PC.
胰腺癌(PC)是癌症死亡的第四大原因,通常直到它已经被诊断出来
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)
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Surinder K. Batra其他文献
Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications
- DOI:
10.1007/s10555-007-9052-4 - 发表时间:
2007-02-02 - 期刊:
- 影响因子:8.700
- 作者:
Murielle Mimeault;Surinder K. Batra - 通讯作者:
Surinder K. Batra
Wolfram 症候群の実態調査
关于 Wolfram 综合征的事实调查
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
Yukihiro Tamura;Michiyo Higashi;Sho Kitamoto;Seiya Yokoyama;Masahiko Osako;Michiko Horinouchi;Takeshi Shimizu;Mineo Tabata;Surinder K. Batra;Masamichi Goto;Suguru Yonezawa;松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生 - 通讯作者:
松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
PP01.05 Targeting MUC16-Mediated KRASi Resistance in NSCLC
PP01.05 针对非小细胞肺癌中 MUC16 介导的 KRASi 耐药性
- DOI:
10.1016/j.jtho.2025.03.013 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:20.800
- 作者:
Ashu Shah;Shamema Salam;Sanjib Chaudhary;Iniyan A. Muthamil;Imayavaramban Lakshmanan;Surinder K. Batra;Apar K. Ganti - 通讯作者:
Apar K. Ganti
Mo1138 COMPARATIVE PROTEOMICS REVEALS TRANSLATIONAL POTENTIAL OF TARGETS FOR PANCREATIC DUCTAL ADENOCARCINOMA
- DOI:
10.1016/s0016-5085(23)02780-4 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:
- 作者:
Mathilde Resell;Hanne-Line Rabben;Manoj Amrutkar;Lars Hagen;Surinder K. Batra;Caroline S. Verbeke;Timothy C. Wang;Duan Chen;Chun-Mei Zhao - 通讯作者:
Chun-Mei Zhao
MUC5AC in stromal heterogeneity and the Progression of Pancreatic Cancer
- DOI:
10.1016/j.canlet.2023.216541 - 发表时间:
2024-01-28 - 期刊:
- 影响因子:
- 作者:
Surinder K. Batra - 通讯作者:
Surinder K. Batra
Surinder K. Batra的其他文献
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{{ truncateString('Surinder K. Batra', 18)}}的其他基金
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
- 批准号:
10557180 - 财政年份:2022
- 资助金额:
$ 50.35万 - 项目类别:
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
- 批准号:
10367553 - 财政年份:2022
- 资助金额:
$ 50.35万 - 项目类别:
Connectivity mapping identified novel combination therapy for glioblastoma
连接映射确定了胶质母细胞瘤的新型联合疗法
- 批准号:
10504826 - 财政年份:2022
- 资助金额:
$ 50.35万 - 项目类别:
Connectivity mapping identified novel combination therapy for glioblastoma
连接映射确定了胶质母细胞瘤的新型联合疗法
- 批准号:
10686268 - 财政年份:2022
- 资助金额:
$ 50.35万 - 项目类别:
Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
- 批准号:
10503433 - 财政年份:2022
- 资助金额:
$ 50.35万 - 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
- 批准号:
10156494 - 财政年份:2021
- 资助金额:
$ 50.35万 - 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
- 批准号:
10339431 - 财政年份:2021
- 资助金额:
$ 50.35万 - 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
- 批准号:
10551280 - 财政年份:2021
- 资助金额:
$ 50.35万 - 项目类别:
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