Exocytic pathways in HNSCC progression

描述（由申请人提供）：最近的研究发现，肿瘤来源的微囊被称为外泌体，由于它们含有复杂的蛋白质和microrna，因此可以作为长距离通信的载体。在头颈部鳞状细胞癌中，与许多其他癌症一样，外泌体的分泌与患者的晚期有关。在大多数情况下，这些囊泡被归类为外泌体，50-100 nm的囊泡已被证明介导进展，转移，生存，耐药，免疫调节和许多其他侵袭性癌症表型。外泌体产生的机制尚不清楚，尽管已知外泌体起源于晚期内吞区。我们最近的初步数据表明，内殖孔是外泌体分泌的部位，相反，规范的内殖孔调节因子影响外泌体分泌。基于这些和其他的发现，我们假设控制入侵足活性和外泌体分泌的胞外晚期内体/溶酶体途径可能是同一种途径。此外，这些途径可能在30-40%携带11q13.3扩增子的HNSCC肿瘤中不受调节，因为我们已经证明11q13扩增的细胞骨架蛋白接触是侵入性活性、外泌体分泌和肿瘤侵袭性的关键调节因子。在本项目中，我们将测试invadopodia是否代表外泌体的对接位点，并确定HNSCC细胞分泌外泌体的关键细胞内调节点。我们还将验证11q13扩增是HNSCC患者外泌体分泌的独立预测因子的假设。最后，我们将确定抑制外泌体分泌是否代表一种可行的治疗策略。

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.