Multiscale Modeling of ECM-tumor interactions in Breast Cancer

描述(申请人提供)：在人类中，通过乳房X光检查发现，乳腺组织致密是发展为浸润性乳腺癌的常见风险因素。这种致密的组织与间质胶原蛋白增多、上皮细胞增多和脂肪组织减少有关。最近对转基因小鼠的研究表明，乳腺间质组织中胶原密度的增加在促进乳腺肿瘤的形成和侵袭性方面起到了致病作用。其他研究表明，细胞外基质(ECM)沉积和/或交联会促进侵袭性、侵袭性细胞表型的下游组织刚性。相反，作为正常和原位癌上皮细胞基础的基底膜ECM蛋白被认为可以抑制肿瘤的进展。由于细胞外基质与肿瘤细胞相互作用的复杂性，用传统的生物学方法很难完全分离和了解细胞外基质在肿瘤进展中的各种作用。因此，我们建议使用一种跨学科的方法，在这种方法中，我们开发了一个基于细胞的三维多尺度数学模型，研究ECM与乳腺癌的相互作用。使用这一模型，我们将在电子计算机实验中测试ECM僵硬和间质胶原纤维化提供促进肿瘤进展和侵袭的环境这一总体假设。我们将专门测试胶原纤维密度、宽度、排列和交联度的作用，以及基底膜细胞外基质和蛋白水解酶在肿瘤生长和侵袭中的作用。所有建模都将与实验完全结合，以获得真实的参数和单独的测试预测。我们期望这一项目将确定促进乳腺癌进展的关键微环境因素，并为未来的治疗干预奠定基础。

DESCRIPTION (provided by applicant): In humans, a common risk factor for the development of invasive breast cancer is dense breast tissue, detected by mammography. This dense tissue is associated with increased stromal collagen, increased epithelial cells, and decreased fatty tissue. Recent studies in transgenic mice indicate that increased collagen density in breast stromal tissue plays a causative role in promoting both the formation and invasiveness of breast tumors. Additional studies implicate tissue rigidity downstream of extracellular matrix (ECM) deposition and/or cross linking in promoting aggressive, invasive cellular phenotypes. Conversely, basement membrane ECM proteins that underlie normal and carcinoma in situ epithelial cells are thought to inhibit tumor progression. Because of the complexity of extracellular matrix-tumor cell interactions, it is difficult to fully isolate and understand the various effects of extracellular matrix on tumor progression using traditional biological approaches. We therefore propose to use an interdisciplinary approach in which we develop a 3-dimensional cell-based multiscale mathematical model of ECM-breast cancer interactions. Using this model, we will perform in silico experiments to test the overall hypothesis that ECM rigidity and stromal collagen fibrosis provide an environment that promotes tumor progression and invasion. We will specifically test the role of collagen fibril density, width, alignment, and crosslinking and the role of basement membrane ECM and proteases on cancer growth and invasion. All modeling will be fully integrated with experimentation to obtain realistic parameters and separately test predictions. We anticipate that this project will identify critical microenvironmental factors promoting breast cancer progression and lay the groundwork for future therapeutic intervention.