A biophysical stromal basis for radiation sensitivity in ductal carcinoma in situ

项目摘要 乳腺癌的演变涉及上皮细胞和周围环境之间复杂的相互作用。 基质微环境。肿瘤进展与细胞外基质的显著重塑有关 (ECM)，这创造了一个有利于入侵和移民的脚手架。改装后的ECM也显著地 比正常僵硬，并促进恶性转化和转移。我们假设ECM僵硬 也调节对治疗的反应。ECM提供了激活钥匙的生化和生物物理线索 决定细胞命运和这些信号的分子通路主要通过整合素家族转导 感受器。事实上，ECM张力增强了整合素的活性，并刺激了PI3-K信号转导 诱导恶性转化，细胞外基质僵硬激活YAP-TAZ转录因子，增强 肿瘤的恶性行为。因此，PI3-k和YAP-TAZ是ECM激活的关键分子 驱动组织恶性行为的机制，并可能提供新的预测机会 预后和治疗靶向。 放射治疗通常用于治疗乳腺癌，然而，对放射治疗机制的了解 基质张力促进阻力的行为是一个创新的研究前沿，但尚未被研究。我们的 初步数据表明，高ECM硬度(4kPa.)可以改变细胞的凋亡和增殖反应 恶性乳腺细胞中的电离辐射(IR)，并揭示这与YAP的激活有关。同样 重要和有趣的是，张力在原位癌治疗抵抗中的作用。导管原位癌 (DCIS)是由位于导管上皮室内的癌细胞组成，没有 但已经侵入了周围的基质。众所周知，细胞外基质的主动重塑发生在 原位病变周围的间质和间质重塑导致组织力量增加和 胶原蛋白--促进进步的交联剂。DCIS样病变的结构提供了独特的 有机会研究驻留在导管中的癌细胞和间质激活之间的相互作用，以及 为此，我们开发了原位疾病模型。 我们推测，激活的ECM间质的高张力在存活和 通过直接参与YAP通路促进癌细胞的增殖，并且 从激活的基质中分离出促进生存的机械信号是一种很有前途的方法。 以提高治疗效果。我们的目标是确定ECM是否以及如何具体地 通过测试1)YAP通路是否在IR中独立起作用来调节IR治疗的耐药性- 介导的细胞死亡和增殖；2)整合素机械信号是否改变这一调节。在……里面 此外，我们有独特的机会调查基质的生物物理和形态特征 在临床DCIS中，YAP信号与疾病进展相关。

Project Summary The evolution of breast cancer involves a complex interplay between the epithelial cells and the surrounding stromal microenvironment. Tumor progression is associated with marked remodeling of the extracellular matrix (ECM), which creates a scaffold that favors invasion and migration. The remodeled ECM is also significantly stiffer than normal, and promotes malignant transformation and metastasis. We hypothesize that ECM stiffness also regulates response to therapy. The ECM provides biochemical and biophysical cues that activate key molecular pathways that direct cell fate and these cues are primarily transduced through the integrin family of receptors. Indeed, ECM tension enhances integrin activity and stimulates PI3-kinase (PI3-k) signaling to induce malignant transition, and ECM stiffness activates the YAP-TAZ transcription factors to enhance the malignant behavior of tumors. As such, PI3-k and YAP-TAZ represent key ECM activated molecular mechanisms that drive the malignant behavior of tissues and could provide novel opportunities for predicting prognosis and therapeutic targeting. Radiation therapy is commonly used to treat breast cancer, however, knowledge of the mechanisms by which stromal tension act to promote resistance is an innovative front of research, and yet uninvestigated. Our preliminary data indicate that high ECM stiffness (4kPa) modifies the apoptotic and proliferative response to ionizing radiation (IR) in malignant breast cells, and reveal that this is associated with YAP activation. Equally important and interesting is the role of tension in therapy resistance in in situ cancer. Ductal carcinoma in situ (DCIS) is comprised of cancerous epithelial cells that reside within the ductal epithelial compartment without yet having invaded into the surrounding stroma. It is well known that active remodeling of the ECM, occurs in the stroma surrounding in situ lesions and that stromal remodeling leads to increased tissue force and collagen-cross-linkingthat drives progression. The architecture of DCIS-like lesions provides unique opportunities to investigate the interplay between cancer cells residing in the duct and stromal activation, and we have developed models of in situ disease for this purpose. We hypothesize that the high tension of an activated ECM stroma plays a critical role in the survival and proliferation of cancerous epithelial cells through direct engagement of the YAP pathways, and that disengaging pro-survival mechanosignaling emanating from the activated stroma is a promising approach towards enhancing therapeutic efficacy. Our goals are to determine if and how ECM tension specifically regulates IR therapy resistance by testing 1) whether the YAP pathways are acting independently in IR- mediated cell death and proliferation; 2) and whether integrin mechanosignaling modifies this regulation. In addition, we have the unique opportunity to investigate whether stromal biophysical and morphological features are associated YAP signaling and disease progression in clinical DCIS.