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

• 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
• 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

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 口腔癌每年在美国造成8,000多人死亡，在全世界造成120,000人死亡。除了 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。超过90%的 口腔癌由口腔鳞状细胞癌（OSCC）引起。 这个项目是基于这样一个前提，即未转化的细胞可以控制邻近细胞的生长。 通过接触归一化转化细胞。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和基因产物， 使癌细胞能够克服这种形式的生长控制，还没有被定义。我们找到那个接头人了 正常化抑制跨膜粘蛋白受体podoplanin（PDPN）下游的表达 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。口腔癌前病变 表达高水平PDPN的病变（例如白斑病）成为癌症的可能性是正常的几倍 而不是不表达PDPN的病变。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 可以用来检测和治疗口腔癌。我们的理论基础是钙粘蛋白连接是 通常在转化细胞之间被破坏，而PDPN表达增强。 PDPN抗体和怀槐种子凝集素（MASL）有效地靶向PDPN，以减少PDPN的表达。 OSCC细胞运动性和活力。此外，MASL是无毒的，并且可以口服给药以抑制肿瘤 在临床前研究中没有显著的副作用。我们假设钙粘蛋白 介导接触正常化以抑制PDPN表达，并且PDPN可以用作功能性调节剂。 协同抑制肿瘤细胞生长和增强抗癌免疫相关化疗靶点 反应我们提出了三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、运动性、Wnt信号传导和PDPN表达。在目标2中， 我们将确定PDPN信号是否能使Src转化的成纤维细胞和OSCC细胞抑制生长， 由邻近的非转化细胞控制。在目标3中，我们将确定MASL是否可以针对PDPN进行扩增 在FDA批准的1期试验中，宿主免疫应答与其抑制OSCC细胞生长的能力一致 口腔癌患者的人体临床试验。 这个项目将使研究生和医学生接触到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。这项工作将提高我们的能力， 检测，预防和治疗口腔癌，以及其他由PDPN信号驱动的癌症。

项目成果

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

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.

• DOI: 10.1186/s12964-021-00817-9
• 发表时间: 2022-02-17
• 期刊: Cell communication and signaling : CCS
• 作者: Sheehan SA;Retzbach EP;Shen Y;Krishnan H;Goldberg GS
• 通讯作者: Goldberg GS