Integrative analysis of molecular and cellular mechanisms underlying therapy failure and local recurrence of head and neck cancers after surgery

头颈癌术后治疗失败及局部复发的分子细胞机制综合分析

• 批准号: 232863538
• 负责人: Professor Dr. Amir Abdollahi, Ph.D.
• 金额: --
• 依托单位: Hals-Nasen-Ohrenheilkunde mit Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/232863538?language=en
• 关键词: Integrative; analysis; molecular; cellular; mechanisms

Head and neck squamous cell cancer (HNSCC) is a common and fatal disease. The poor survival of patients afflicted with these cancers is mostly a consequence of recurrent disease. Within our previous work, we developed an orthotopic mouse tumor model as a pre-clinical experimental platform to study local recurrence formation after surgery. Using an un-supervised multilevel (protein, mRNA, and miRNA) strategy, we found that in contrast to primary tumors, recurrent head and neck tumor cells undergo a stable genetic conversion towards a less proliferative but invasive and anti-apoptotic phenotype (i.e. up-regulation of u-PA, SMRA3; down-regulation of Mybbp1a, caspase 3, Ki67, miR 106a, miR 196b). Further functional studies provided experimental evidence that certain proteins (i.e. FOXM1, Mybbp1a) govern the switch between an invasive and proliferative phenotype. Based on these data, we hypothesize on the presence of a critical subpopulation of tumor cells (recurrent tumor initiating cells (R-TIC)) with the above-described features that give rise to post-surgical recurrence. Therefore, we intend to focus on two topics within our joint research project: First, we plan to confirm the role of identified key molecular circuitries that govern the switch of tumor cells from proliferation to invasion. Second, we will trace the progress of the invasive residual tumor cell populations that may contain R-TICs after surgery on a molecular level into macroscopic recurrent tumors and characterize the role of the above named and possibly novel circuitries in this process.

头颈部鳞状细胞癌（HNSCC）是一种常见的致命疾病。这些癌症患者的低生存率主要是疾病复发的结果。在我们之前的工作中，我们开发了一个原位小鼠肿瘤模型作为临床前实验平台来研究手术后局部复发的形成。使用无监督的多水平（蛋白质、mRNA和miRNA）策略，我们发现与原发肿瘤相比，复发性头颈部肿瘤细胞经历稳定的遗传转化，向低增殖但侵袭性和抗凋亡表型转变（即u-PA、SMRA3上调；Mybbp1a、caspase 3、Ki67、miR 106a、miR 196b下调）。进一步的功能研究提供了实验证据，证明某些蛋白质（如FOXM1， Mybbp1a）控制着侵袭性和增殖性表型之间的转换。基于这些数据，我们假设存在一个关键的肿瘤细胞亚群（复发性肿瘤起始细胞（R-TIC）），具有上述特征，导致术后复发。因此，我们打算在我们的联合研究项目中重点关注两个主题：首先，我们计划确认已确定的关键分子电路在控制肿瘤细胞从增殖到侵袭的转换中的作用。其次，我们将在分子水平上追踪手术后可能含有r - tic的侵袭性残留肿瘤细胞群向宏观复发肿瘤的进展，并表征上述命名的可能新颖的电路在这一过程中的作用。

项目成果

Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.

• DOI: 10.1016/j.ejca.2016.01.003
• 发表时间: 2016-04
• 期刊: European journal of cancer
• 影响因子: 8.4
• 作者: I. Tinhofer;I. Tinhofer;V. Budach;V. Budach;Mohammad Saki;Mohammad Saki;R. Konschak;R. Konschak-R.-Ko

Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

• DOI: 10.1080/15592294.2015.1137414
• 发表时间: 2016-01-02
• 期刊: EPIGENETICS
• 影响因子: 3.7
• 作者: Kostareli, Efterpi;Hielscher, Thomas;Hess, Jochen
• 通讯作者: Hess, Jochen