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

头颈部鳞状细胞癌是一种常见而致命的疾病。患有这些癌症的患者的生存率低主要是疾病复发的结果。在我们之前的工作中，我们开发了原位小鼠肿瘤模型作为临床前实验平台，以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，我们发现与原发性肿瘤相比，复发性头颈部肿瘤细胞经历稳定的遗传转化，向增殖性较低但具有侵袭性和抗凋亡表型转变（即u-PA，SMRA 3上调; Mybbp 1a，caspase 3，Ki 67，miR 106 a，miR 196 b下调）。进一步的功能研究提供了实验证据，表明某些蛋白质（即FOXM 1，Mybbp 1a）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专注于两个主题：首先，我们计划确认已确定的控制肿瘤细胞从增殖到侵袭的关键分子电路的作用。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进展为肉眼可见的复发性肿瘤，并表征上述命名的和可能的新电路在此过程中的作用。

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.