Investigating Breast Cancer Collective Invasion

描述(申请人提供)：在肿瘤进展过程中，乳腺的有序结构被破坏，因为过度增殖的细胞聚集在导管和小叶的管腔空间。随着时间的推移，肿瘤细胞可以侵入基质，在那里它们可以进入血管系统，并扩散到全身较远的部位。尽管诱导侵袭性生长是转移级联过程中的关键一步，但乳腺癌细胞如何变得侵袭性仍然知之甚少。利用器官类型培养系统和动物模型，我们建议确定(1)在集体侵袭过程中细胞内信号通路如何调节细胞运动；(2)乳腺成纤维细胞如何诱导集体侵袭；(3)肿瘤细胞亚群如何触发集体侵袭。破译乳腺癌侵袭的要求可以确定在肿瘤和微环境中进行治疗干预的目标。 公共卫生相关性：远处转移是几乎所有乳腺癌患者死亡的原因。导致转移的关键步骤是肿瘤细胞向结缔组织的侵袭。我们将研究肿瘤细胞是如何变得侵袭的，目的是更准确地确定哪些患者有发生转移的风险，并确定治疗干预的目标。

DESCRIPTION (provided by applicant): During tumor progression the well-ordered architecture of the mammary gland becomes disrupted as hyperproliferative cells accumulate in the luminal space of ducts and lobules. Over time the neoplastic cells can invade into the stroma where they can access the vasculature system and disseminate to distant sites throughout the body. Although the induction of invasive growth is a key step in the metastatic cascade, how breast cancer cells become invasive remains poorly understood. Using an organotypic culture system and animal models we propose to determine (1) how cell motility is regulated by intracellular signaling pathways during collective invasion; (2) how mammary fibroblasts induce collective invasion and (3) how subpopulations of neoplastic cells trigger collective invasion. Deciphering the requirements for breast cancer invasion could identify targets for therapeutic intervention in both the tumor and the microenvironment. PUBLIC HEALTH RELEVANCE: Distant metastases are responsible for nearly all breast cancer patient deaths. A critical step leading to the development of metastases is the invasion of tumor cells into connective tissue. We will investigate how tumor cells become invasive with the goals of more accurately identifying which patients are at risk of developing metastases and identifying targets of therapeutic intervention.