Intra-tumoral neurons contribute to head and neck cancer pain

项目摘要/摘要 疼痛是影响头颈癌患者生存的独立预后因素。这些癌症可能是 大致分为由感染高危人乳头瘤病毒(HPV阳性)和 那些突变驱动的(HPV阴性)。口腔面部疼痛的发作可能预示着癌前病变 癌变以及疾病复发，提示有预测价值。因此，疼痛是一种 在HNC中有显著的共病。尽管如此，HNC疼痛管理方面还缺乏完善的指南 阿片类药物仍然处于治疗的前沿。考虑到它对患者生存的影响和广泛的风险 对于阿片类药物依赖，需要额外的治疗来解决HNC疼痛。脑内神经元的存在 实体肿瘤现在被广泛接受。我们的初步数据显示，HPV阴性肿瘤明显多于 比HPV阳性的同龄人更容易神经过敏。此外，我们还表明，肿瘤内神经元 在转录和功能上与正常(幼稚)神经元不同。在目标1中，我们将测试HPV状态 性别影响肿瘤内神经元的这些特征及其对癌症疼痛的影响。我们有 以前发表的研究表明，肿瘤释放的小细胞外小泡(SEV)将神经元吸引到肿瘤床上。我们的 对SEV miRNAs的初步分析表明，这些货物分子直接影响肿瘤的神经支配。在……里面 此外，我们还表明，HNC癌基因的表达影响了miRNAs在SEV中的包装。在AIM 2，我们将在体内检测SEV miRNAs对癌痛的影响。此外，考虑到大脑中神经元的存在 肿瘤组织，我们对HNC患者肿瘤切片的电生理活性进行了评估。我们发现人乳头瘤病毒 阴性肿瘤的电活动明显高于HPV阳性肿瘤。我们还展示了 这种活性可通过止痛药(如利多卡因)在药理上减弱。在《目标3》中，我们将 使用疼痛评估患者问卷和匹配的患者肿瘤来确定肿瘤电信号 活动与患者报告的疼痛相关。我们还将测试减轻疼痛的药物是否也能起到 在体内减缓/阻止肿瘤生长。总而言之，这些研究的结果将确定肿瘤内神经元 肿瘤释放的SEV是HNC疼痛的关键驱动因素。此外，我们将确定神经靶向药物 这可以抑制肿瘤生长并提高存活率。这些发现将支持未来的临床试验测试 这些靶点和药物用于控制癌症疼痛。

Project Summary/Abstract Pain is an independent prognostic factor for survival in head and neck cancer (HNC). These cancers can be broadly divided into those that are induced by infection with high-risk human papillomavirus (HPV positive) and those that are mutationally driven (HPV negative). The onset of orofacial pain may signal the pre-cancerous to cancerous transition as well as the recurrence of disease, suggesting a predictive value. Thus, pain is a significant co-morbidity in HNC. Despite this, well-established guidelines for HNC pain management are lacking and opioids remain at the forefront of treatment. Given its influence on patient survival and the widespread risk of opioid dependence, additional therapies are needed to address HNC pain. The presence of neurons within solid tumors is now widely accepted. Our preliminary data show that HPV negative tumors are significantly more innervated than their HPV positive counterparts. Moreover, we show that intra-tumoral neurons are transcriptionally and functionally different from normal (naïve) neurons. In Aim 1, we will test how HPV status and sex influence these characteristics of intra-tumoral neurons and their effects on cancer pain. We have previously published that tumor-released small extracellular vesicles (sEVs) lure neurons to the tumor bed. Our preliminary analysis of sEV miRNAs suggest that these cargo molecules directly impact tumor innervation. In addition, we also show that expression of HNC oncogenes influences the packaging of miRNAs in sEVs. In Aim 2, we will test the effect of sEV miRNAs on cancer pain in vivo. In addition, given the presence of neurons within tumor tissues, we electrophysiologically assessed activity in HNC patient tumor slices. We found that HPV negative tumors harbor a significantly higher electrical activity than those that are HPV positive. We also show that this activity can be pharmacologically attenuated with pain-targeting drugs (e.g. lidocaine). In Aim 3, we will use a pain assessment patient questionnaire and matched patient tumors to determine whether tumoral electrical activity correlates with patient reported pain. We will also test whether drugs that attenuate pain also function to slow/block tumor growth in vivo. Together, the outcomes of these studies will define that intra-tumoral neurons and tumor-released sEVs as critical drivers of HNC pain. Moreover, we will have identified nerve targeting drugs that can attenuate tumor growth and improve survival. These findings will support future clinical trials testing these targets and drugs for the control of cancer pain.