Investigating Breast Cancer Collective Invasion

描述（由申请人提供）：在肿瘤进展过程中，随着超增殖细胞在导管和小叶的腔隙中积聚，乳腺的有序结构被破坏。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的远处部位。虽然诱导浸润性生长是转移级联的关键步骤，但乳腺癌细胞如何变得浸润性仍然知之甚少。使用器官型培养系统和动物模型，我们建议确定(1)在集体入侵期间细胞运动如何通过细胞内信号通路调节；(2)乳腺成纤维细胞如何诱导集体侵袭；(3)肿瘤细胞亚群如何引发集体侵袭。破译乳腺癌侵袭的要求可以在肿瘤和微环境中确定治疗干预的靶点。

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.