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Cadherins, contact normalization, and targeting podoplanin to treat oral cancer

钙粘蛋白、接触正常化和靶向平足蛋白治疗口腔癌

基本信息

批准号：
10437217
负责人：
GARY S GOLDBERG
金额：
$ 48.3万
依托单位：
ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
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：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437217
关键词：
Adherens Junction Antibodies Basic Science Biological Markers Cadherins Cancer Etiology Cancer Patient Cancer Survivor Cell Culture Techniques Cell Survival Cells Cellular Morphology Cellular biology Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Contracts Cytotoxic agent Environment FDA approved Fibroblasts Future Genes Growth Human Immune Immune response Infiltration Inflammation Institution Institutional Review Boards Instruction Lectin Lesion Leukoplakia Maackia amurensis Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mediating Medical Students Molecular Biology Morphology Normal Cell Oncogenic Oral Patients Persons Phase Phase I Clinical Trials Physicians Process Quality of life Reagent Research Scientist Seeds Side Signal Transduction Survival Rate Survivors Technology Testing Time Vascularization WNT Signaling Pathway Work anti-cancer base cancer cell cell growth cell motility cell transformation chemotherapy clinical translation ena protein established cell line genetic corepressor graduate student homologous recombination immune cell checkpoints malignant mouth neoplasm mammary mortality mouth squamous cell carcinoma mucin receptor neoplastic cell oral lesion podoplanin preclinical study premalignant prevent refractory cancer side effect src-Family Kinases transcriptome tumor tumor growth tumor progression

项目摘要

Summary Oral cancer kills over 8,000 people in the USA and 120,000 people worldwide every year. In addition to this mortality, oral cancer survivors suffer from permanent sequelae and decreased quality of life. Over 90% of oral cancers are caused by oral squamous cell carcinoma (OSCC). This project is based on the premise that nontransformed cells can control the growth of neighboring transformed cells by contact normalization. Direct contact between transformed and nontransformed cells is required for this process. However, junctions responsible for contact normalization, and gene products that enable cancer cells to overcome this form of growth control, have not been defined. We found that contact normalization suppresses expression of the transmembrane mucin receptor podoplanin (PDPN) downstream of oncogenic Src tyrosine kinase activity. Many cancer cells, including OSCCs, express PDPN to promote cancer progression. Precancerous oral lesions (e.g. leukoplakia) that express high levels of PDPN are several times more likely to become cancers than lesions that do not express PDPN. In addition, PDPN has been identified as an immune cell checkpoint corepressor. Indeed, PDPN has emerged as a functionally relevant biomarker and chemotherapeutic target that can be used to detect and treat oral cancer. Our rationale is based on the fact that cadherin junctions are often disrupted between transformed cells, while PDPN expression is enhanced. PDPN antibodies and Maackia amurensis seed lectin (MASL) efficiently target PDPN to decrease OSCC cell motility and viability. Moreover, MASL is nontoxic and can be administered orally to inhibit tumor growth and vascularization without notable side effects in preclinical studies. We hypothesize that cadherins mediate contact normalization to suppress PDPN expression, and PDPN can be utilized as a functionally relevant chemotherapeutic target to synergistically inhibit tumor cell growth and augment anticancer immune response. We propose 3 Specific Aims to test this hypothesis. In Aim 1, we will determine if cadherins are needed for nontransformed cells to normalize morphology, growth, motility, Wnt signaling, and PDPN expression of adjacent Src transformed and OSCC cells. In Aim 2, we will determine if PDPN signaling enables Src transformed fibroblasts and OSCC cells to override growth control by neighboring nontransformed cells. In Aim 3, we will determine if MASL can target PDPN to augment host immune response in concert with its ability to inhibit OSCC cell growth in an FDA approved Phase 1 human clinical trial on oral cancer patients. This project will expose graduate and medical students to basic research in molecular and cell biology to elucidate fundamental mechanisms behind contact normalization. This work will enhance our abilities to detect, prevent, and treat oral cancer, as well as other cancers that are driven by PDPN signaling.

总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Independent effects of Src kinase and podoplanin on anchorage independent cell growth and migration.

DOI：
10.1002/mc.23410
发表时间：
2022-07
期刊：
Molecular carcinogenesis
影响因子：
4.6
作者：
通讯作者：

Maackia amurensis seed lectin (MASL) ameliorates articular cartilage destruction and increases movement velocity of mice with TNFα induced rheumatoid arthritis.

DOI：
10.1016/j.bbrep.2022.101341
发表时间：
2022-12
期刊：
BIOCHEMISTRY AND BIOPHYSICS REPORTS
影响因子：
2.7
作者：
Hamilton, Kelly L.;Greenspan, Amanda A.;Shienbaum, Alan J.;Fischer, Bradford D.;Bottaro, Andrea;Goldberg, Gary S.
通讯作者：
Goldberg, Gary S.

Heterocellular N-cadherin junctions enable nontransformed cells to inhibit the growth of adjacent transformed cells.