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.

概括口腔癌每年在美国夺去 8,000 多人的生命，在全球夺去 120,000 人的生命。此外由于这种死亡率，口腔癌幸存者遭受永久性后遗症和生活质量下降。 90%以上口腔癌是由口腔鳞状细胞癌（OSCC）引起的。该项目基于这样的前提：未转化细胞可以控制邻近细胞的生长通过接触标准化转化细胞。转化细胞和非转化细胞之间的直接接触是此过程所需的。然而，负责接触正常化的连接点和基因产物癌细胞能否克服这种形式的生长控制，目前尚未确定。我们找到了那个联系方式正常化抑制下游跨膜粘蛋白受体足足蛋白 (PDPN) 的表达致癌 Src 酪氨酸激酶活性。许多癌细胞，包括 OSCC，表达 PDPN 以促进癌症进展。口腔癌前期表达高水平 PDPN 的病变（例如白斑）罹患癌症的可能性高出数倍与不表达 PDPN 的病变相比。此外，PDPN已被确定为免疫细胞检查点辅阻遏物。事实上，PDPN 已成为功能相关的生物标志物和化疗靶点可用于检测和治疗口腔癌。我们的基本原理是基于钙粘蛋白连接是这样的事实：转化细胞之间经常被破坏，而 PDPN 表达则增强。 PDPN 抗体和山槐种子凝集素 (MASL) 有效靶向 PDPN，以减少 OSCC 细胞运动性和活力。此外，MASL无毒，可以口服抑制肿瘤在临床前研究中，生长和血管化没有明显的副作用。我们假设钙粘蛋白介导接触正常化以抑制 PDPN 表达，并且 PDPN 可用作功能性相关化疗靶点协同抑制肿瘤细胞生长并增强抗癌免疫回复。我们提出 3 个具体目标来检验这一假设。在目标 1 中，我们将确定非转化细胞是否需要钙粘蛋白来使形态正常化，相邻 Src 转化细胞和 OSCC 细胞的生长、运动、Wnt 信号传导和 PDPN 表达。在目标 2 中，我们将确定 PDPN 信号传导是否能够使 Src 转化的成纤维细胞和 OSCC 细胞抑制生长受邻近非转化细胞的控制。在目标 3 中，我们将确定 MASL 是否可以针对 PDPN 进行增强在 FDA 批准的第一阶段中，宿主免疫反应与其抑制 OSCC 细胞生长的能力相一致针对口腔癌患者的人体临床试验。该项目将使研究生和医学生接触分子和细胞生物学的基础研究阐明接触正常化背后的基本机制。这项工作将增强我们的能力检测、预防和治疗口腔癌以及由 PDPN 信号驱动的其他癌症。

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.