The Role of SPON1 Expressing Inflammatory Monocytes in Promoting Lung Cancer Metastasis.

摘要 肺癌是美国癌症相关死亡的主要原因，2019年死亡142,670人。 肺鳞状细胞癌（LUSC）是非小细胞肺癌（NSCLC）的主要亚型。炎性 LUSC中单核细胞（IM）浸润与较高的死亡率相关。使用LUSC小鼠模型， 我们的实验室发现，CCL 2介导的IM募集对于LUSC转移是必要和充分的。 来自我们的LUSC小鼠模型的初步RNA-seq数据鉴定了荷瘤IM中Spon 1的上调 与健康小鼠的IM相比。Spon 1是神经系统发育的轴突导向分子。 因此，我建议，神经元轴突招募到肿瘤的IM。前列腺癌的研究 研究表明，神经支配增加的患者的癌症生长和转移增加， 预后虽然研究表明，随着神经募集的增加，预后更差，但神经募集的机制可能与神经再生有关。 招聘不明确。鉴于Spon 1与组织重塑和神经支配有关， 神经发生通过神经元轴突介导转移，我们假设：（i）IM释放SPON 1进入 TME和（ii）SPON 1通过向肿瘤募集神经元轴突驱动LUSC转移。我提议 通过以下目的来检验这一假设：（1）确定SPON 1 + IM在轴突募集中的作用 进入TME。2.）确定SPON 1 + IM在LUSC肿瘤进展和转移中的作用。这 该项目将在两个有价值的学科之间建立一个重要的交叉点，以研究IM是如何作为 免疫系统可能正在招募神经元轴突进入肿瘤，以驱动LUSC转移和疾病 进展这种理解将为开发针对SPON 1的靶向治疗方法铺平道路， 或者肿瘤内特定种类的神经元。这个项目有可能产生有意义的影响 为患者打开通向多个治疗靶点的大门。此外，我相信这个项目和我的 一个全面的培训计划将使我从F到K到R的管道开始，为我的成功职业生涯做好准备 一个独立资助的科学家兼医生

ABSTRACT Lung cancer is the leading cause of cancer-related death in the U.S., accounting for 142,670 deaths in 2019. Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancers (NSCLC). Inflammatory monocyte (IM) infiltration in LUSC is associated with higher mortality. Using LUSC mouse models developed in our lab, we found that CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Preliminary RNA-seq data from our LUSC mouse models identify Spon1 upregulation in tumor bearing IMs compared to IMs from healthy mice. Spon1 is an axonal guidance molecule for the developing nervous system. Thus, I propose that neuronal axons are recruited into the tumor by IMs. Studies in prostate cancer have demonstrated that patients with increased innervation have increased cancer growth and metastasis and poor prognosis. While studies have shown worse prognosis with increased nerve recruitment, the mechanisms of recruitment are unclear. Given that Spon1 is associated with tissue remodeling and innervation, and that tumor neurogenesis mediates metastasis through neuronal axons, we hypothesize that (i) IMs release SPON1 into the TME and (ii) SPON1 drives LUSC metastasis through the recruitment of neuronal axons to the tumor. I propose to test this hypothesis through the following aims: 1.) Determine the role of SPON1+ IMs on recruitment of axons into the TME. 2.) Determine the role of SPON1+ IMs have on LUSC tumor progression and metastasis. This project will create an important intersection between two valuable disciplines to study how IMs, a component of the immune system, may be recruiting neuronal axons into the tumor to drive LUSC metastasis and disease progression. This understanding will then lend way for the development of targeted therapeutics against SPON1, IMs or specific classes of neurons within the tumor. This project has the potential to create a meaningful impact for patients by opening the door to multiple therapeutic targets. Furthermore, I believe this project and my comprehensive training plan will prepare me for a successful career by starting me on the F-to-K-to-R pipeline of an independently funded physician-scientist.