Exocytic pathways in HNSCC progression

描述(申请人提供)：最近的研究已经确认，肿瘤来源的微囊称为外切体，由于它们含有复杂的蛋白质和microRNAs，可以作为远程通讯的工具。在头颈部鳞状细胞癌中，就像许多其他癌症一样，外泌体的分泌与晚期患者有关。在大多数情况下，这些囊泡被归类为外体，50-100 nm的囊泡，已被证明参与调节进展、转移、生存、耐药、免疫调节和许多其他侵袭性癌症表型。虽然已知外切体是从晚期的内吞体内产生的，但对外切体产生的机制知之甚少。我们最近的初步数据表明，内生生物是外切体分泌的部位，相反，规范的内生生物调节因子会影响外周体的分泌。基于这些和其他发现，我们推测，控制不定形吸虫活动和外切体分泌的胞外晚期内切酶/溶酶体途径可能是相同的。此外，在30%-40%携带11q13.3扩增扩增的HNSCC肿瘤中，这些通路可能是不受调控的，因为我们已经证明，11q13扩增的细胞骨架蛋白Cortactin是内陷活性、外体分泌和肿瘤侵袭性的关键调节因子。在这个项目中，我们将测试内陷是否代表外切体的对接位置，并确定HNSCC细胞外切体分泌的关键细胞内调节点。我们还将检验11q13扩增是HNSCC患者外显体分泌的独立预测因子的假设。最后，我们将确定抑制外切体分泌是否代表了HNSCC的可行治疗策略。

DESCRIPTION (provided by applicant): Recent studies have identified tumor-derived microvesicles called exosomes as vehicles for long-distance communication, due to their complex content of proteins and microRNAs. In head and neck squamous cell carcinoma, as in many other cancers, exosome secretion is associated with advanced patient stage. In most cases, those vesicles are classified as exosomes, 50-100 nm vesicles that have been shown to mediate progression, metastasis, survival, drug resistance, immune modulation, and many other aggressive cancer phenotypes. The mechanisms by which exosomes are generated are poorly understood, although exosomes are known to derive from a late endocytic compartment. Our recent preliminary data suggest that invadopodia are sites of exosome secretion and that, conversely, canonical invadopodia regulators affect exosome secretion. Based on these and other findings, we hypothesize that exocytic late endosomal/lysosomal pathways that govern invadopodia activity and exosome secretion may be one and the same. Furthermore, these pathways are likely to be unregulated in the 30-40% of HNSCC tumors that carry amplification of the 11q13.3 amplicon, since we have shown that the 11q13-amplified cytoskeletal protein cortactin is a key regulator of invadopodia activity, exosome secretion, and tumor aggressiveness. In this project, we will test whether invadopodia represent docking sites for exosomes and identify key intracellular regulatory points for exosome secretion by HNSCC cells. We will also test the hypothesis that 11q13-amplification is an independent predictor of exosome secretion in HNSCC patients. Finally, we will determine whether inhibition of exosome secretion represents a viable therapeutic strategy in HNSCC.