Exocytic pathways in HNSCC progression

描述（由申请人提供）：最近的研究已经确定了称为外泌体的肿瘤衍生微泡作为长距离通信的载体，因为它们含有复杂的蛋白质和microRNA。在头颈部鳞状细胞癌中，与许多其他癌症一样，外泌体分泌与晚期患者阶段相关。在大多数情况下，这些囊泡被归类为外泌体，即50-100 nm的囊泡，已显示其介导进展、转移、存活、耐药性、免疫调节和许多其他侵袭性癌症表型。外泌体产生的机制知之甚少，尽管已知外泌体来源于晚期内吞隔室。我们最近的初步数据表明，侵入伪足是外泌体分泌的网站，相反，典型的侵入伪足调节剂影响外泌体分泌。基于这些和其他的发现，我们假设，外泌晚期内体/溶酶体途径，支配侵入伪足活动和外泌体分泌可能是一个和相同的。此外，这些途径在30-40%携带11q13.3扩增子扩增的HNSCC肿瘤中可能是不受调节的，因为我们已经表明11 q13扩增的细胞骨架蛋白corneum是侵袭伪足活性、外泌体分泌和肿瘤侵袭性的关键调节因子。在这个项目中，我们将测试侵入伪足是否代表外泌体的对接位点，并确定HNSCC细胞外泌体分泌的关键细胞内调控点。我们还将检验11 q13扩增是HNSCC患者外泌体分泌的独立预测因子的假设。最后，我们将确定外泌体分泌的抑制是否代表HNSCC中可行的治疗策略。

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.