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

摘要 美国每年有8000多人死于口腔癌，全球每年有12万人死于口腔癌。除了……之外 这种死亡，口腔癌幸存者遭受永久性后遗症和生活质量下降。90%以上的 口腔癌由口腔鳞状细胞癌(OSCC)引起。 这个项目的前提是，未转化的细胞可以控制邻近细胞的生长 通过接触正常化转化细胞。转化细胞和未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 使癌细胞克服这种形式的生长控制，还没有定义。我们找到了那个联系人 正常化抑制下游跨膜粘蛋白受体泊多普宁(PDPN)的表达 致癌的Src酪氨酸激酶活性。 许多癌细胞，包括口腔鳞状细胞癌，表达PDPN以促进癌症的进展。癌前口腔 表达高水平PDPN的病变(如白斑)转化为癌症的可能性要高出几倍 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 辅酶抑制因子。事实上，PDPN已经成为一种功能相关的生物标记物和化疗靶点 可以用来检测和治疗口腔癌。我们的理论基础是钙粘素连接是基于 通常在转化的细胞之间中断，而PDPN的表达增强。 PDPN抗体和山景天种子凝集素(MASL)有效靶向降低PDPN 口腔鳞状细胞癌细胞活力和存活率。此外，MASL是无毒的，可以口服抑制肿瘤 在临床前研究中，生长和血管形成没有明显的副作用。我们假设钙粘附素 中介接触正常化以抑制PDPN的表达，PDPN可用作功能 协同抑制肿瘤细胞生长增强抗癌免疫的相关化疗靶点 回应。我们提出了三个具体目标来检验这一假说。 在目标1中，我们将确定未转化细胞是否需要钙粘附素来使形态正常化， 邻近的Src转化细胞和口腔鳞癌细胞的生长、运动、Wnt信号和PDPN表达。在目标2中， 我们将确定PDPN信号是否使Src转化的成纤维细胞和口腔鳞癌细胞抑制生长 由相邻的未转化细胞控制。在目标3中，我们将确定MASL是否可以针对PDPN进行增强 在FDA批准的第一阶段中，宿主免疫反应与其抑制口腔鳞癌细胞生长的能力相一致 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。

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.