MT-MMP/DDR cross talk at the tumor cell-matrix interface and cancer progression

我们长期的研究是了解蛋白水解物的功能贡献 癌症进展的系统。我们关注的是膜型的作用-- 基质金属蛋白酶(MT-MMPs)通过以下途径促进侵袭活性 组织屏障，特别是MT1-MMP(MMP14)。我们现在展示一种新的交互方式 在MT-MMP家族的三个成员之间，MT1-(MMP14)，MT2-(MMP15)，和 MT3-(MP16)MP(这里称为MT-MMPs)和Discoidin结构域 受体(DDR)，一组独特的受体酪氨酸激酶(RTK)，它们是特异性的 胶原蛋白的激活与MT-MMPs的胶原酶活性 可能在肿瘤细胞扩散过程中协调蛋白分解和黏附程序。 初步数据显示MT-MMP之间存在独特的功能和特异性关系 以及导致胶原蛋白诱导的DDR(DDR1和DDR2)下调的DDR 激活超越受体裂解的过程。的确，MT-MMPs 有选择地切割DDR1，但不切割DDR2。我们还报告了DDR1的逐渐丧失 在浸润性乳腺癌中的表达提示DDR1在这一转变中的作用 从原位癌到浸润性癌。由于DDR1被牵连到 正常乳腺上皮功能和DDR2可能与间充质病变有关。 与表型相似，我们假设MT-MMP对DDR的不同调控可能 会破坏正常的乳房组织结构和功能，导致 恶性肿瘤。为了验证这一假设，我们提出了三个具体目标：1) 研究其结构基础、分子机制和功能后果 DDR/MT-MMP的相互作用，2)研究DDR和MT1-MMP在卵巢癌组织中的表达 3)研究DDR/MT1-MMP3在乳腺癌组织中的相互作用。 乳腺上皮-基质相互作用的实验模型。这方面的研究 应用将填补我们在了解DDR规则和 功能，并将阐明它们与MT-MMPs的相互作用如何影响细胞 正常和恶性乳腺上皮的行为。我们希望这一新知识 将有助于开发更好的治疗和诊断策略，以提高患者的存活率 乳腺癌患者。

The long term of our studies is to understand the functional contribution of proteolytic systems to cancer progression. We have focused on the action of membrane type- matrix metalloproteinases (MT-MMPs) known to promote pro-invasive activity through tissue barriers, particularly MT1-MMP (MMP14). We now show a novel interaction between three members of the MT-MMP family, MT1- (MMP14), MT2- (MMP15), and MT3- (MP16) MP (refered here to as MT-MMPs), and the discoidin domain receptors (DDRs), a unique set of receptor tyrosine kinases (RTKs) that are specifically activated in response to collagen, which together with MT-MMPs' collagenolytic activity may orchestrate the proteolytic and adhesive programs during tumor cell dissemination. Preliminary data show a unique functional and specific relationship between MT-MMPs and DDRs that leads to downregulation of collagen-evoked DDR (DDR1 and DDR2) activation in a process that goes beyond receptor cleavage. Indeed, MT-MMPs selectively cleave DDR1 but not DDR2. We also report a gradual loss of DDR1 expression in invasive breast carcinomas suggesting a role for DDR1 in the transition from in situ to invasive carcinoma. Since DDR1 has been implicated in maintenance of normal mammary epithelial function and DDR2 may be associated with mesenchymal- like phenotypes, we posit that a differential regulation of DDRs by MT-MMPs may contribute to the disruption of normal breast tissue architecture and function that leads to malignant cancer. To test this hypothesis we propose thre Specific Aims: 1) To investigate the structural bases, molecular mechanisms, and functional consequences of DDR/MT-MMP interactions, 2) To investigate the expression of DDRs and MT1-MMP in human breast cancer tissues, and 3) To Investigate the DDR/MT1-MMP interplay in experimental models of breast epithelial-matrix interactions. The studies in this application will fill a wide gap of knowledge on our understanding of DDR regulation and function, and wil shed light on how their interactions with MT-MMPs influence cell behavior in normal and malignant breast epithelium. We hope that this new knowledge will help to develop better therapeutic and diagnostic strategies to improve survival in breast cancer patients.