Type III Collagen as a suppressor of breast cancer progression and metastasis

乳腺癌是女性最常被诊断出的癌症，也是女性癌症的主要原因。 全球范围内的相关死亡。在大多数患者中，死亡不是由原发肿瘤引起的，而是由 转移瘤。值得注意的是，恶性乳腺细胞与肿瘤周围间质之间的相互作用 在乳腺肿瘤的发展过程中起着关键作用。我们的数据支持间质III型的假设 胶原蛋白(Col3)在抑制乳腺癌进展中发挥着新的重要作用。具体地说，我们的 研究表明，与COL3单倍体缺陷(COL3+/-)小鼠相比，COL3单倍体不足(COL3+/-)小鼠发生更多转移 野生型产仔小鼠，这些缺乏Col3的小鼠更容易发生侵袭性的局部复发。 Col3导向治疗预防局部和远处复发的可能性得到了我们以下能力的支持 抑制人和鼠三重阴性乳腺癌模型体外侵袭行为的实验研究 并在体内通过外源Col3的应用。这一提议的中心假设是COL3 通过直接抑制侵袭性来预防乳腺癌的转移和局部复发 乳腺癌细胞的行为和防止肿瘤允许的间质的形成。 确定COL3缺失是侵袭性TNBC行为的生物驱动因素可以显著改善患者 结果：1)最终利用区域Col3相关间质信号作为预后生物标志物 对患者进行风险分层，从而防止低风险患者过度治疗和2)发生含有CO3的疾病 生物材料作为一种减少高危患者TNBC复发的无毒疗法。在这项提案中，我们将 确定COL3区域缺失是否与侵袭和已建立的肿瘤允许间质相关 人类TNBC活检的特征(AIM 1)以及是否通过新的生物材料将Col3输送到乳腺癌 切除部位将提供安全、有效的策略，以限制或消除侵袭性癌症的局部再生长和 转移(目标2)。综上所述，这项工作将提供对Col3在调节 乳腺癌的进展，这可能与许多其他类型的转移和局部侵袭性有关 各种形式的癌症。因为含有Col3的生物材料已经在人类身上安全地用于其他 再生性疗法，拟议的高风险/高影响研究有可能迅速产生独特的 可翻译和安全的诊断和治疗工具，以改善患者的护理质量和预后 患有乳腺癌。

Breast cancer is the most frequently diagnosed cancer in women and is the leading cause of female cancer- related deaths worldwide. In the majority of patients, death is not caused by the primary tumor but rather by metastases. Notably, interactions between malignant mammary cells and the surrounding peritumor stroma play a critical role in mammary tumor progression. Our data support the hypothesis that stromal type III collagen (Col3) plays a novel and important role in suppressing breast cancer progression. Specifically, our studies indicate that Col3 haploinsufficient (Col3+/-) mice develop significantly more metastases compared to wild-type littermates and that these Col3-deficient mice are more susceptible to aggressive local recurrence. The potential for Col3-directed therapies to prevent local and distant recurrence is supported by our ability to suppress aggressive behaviors of both murine and human triple negative breast cancer (TNBC) models in vitro and in vivo through application of exogenous Col3. The central hypothesis of this proposal is that Col3 prevents breast cancer metastasis and local recurrence by directly suppressing the aggressive behavior of breast cancer cells and preventing the formation of a tumor-permissive stroma. Identification of Col3 loss as a biologic driver of aggressive TNBC behaviors could dramatically improve patient outcomes by 1) ultimately exploiting regional Col3-associated stromal signatures as a prognostic biomarker to risk stratify patients, thus preventing overtreatment of low-risk patients and 2) developing Col3-containing biomaterials as a non-toxic therapy to decrease TNBC recurrence in high-risk patients. In this proposal, we will determine whether regional loss of Col3 is associated with invasion and established tumor permissive stromal features in human TNBC biopsies (Aim 1) and whether delivering Col3 via novel biomaterials to breast cancer resection sites will provide a safe, effective strategy to limit or eliminate aggressive cancer local regrowth and metastasis (Aim 2). Together, this work will provide unique insight into the role of Col3 in regulating progression of breast cancer, which may be relevant to many other types of metastatic and locally aggressive forms of cancers. Because Col3-containing biomaterials have been used safely in humans for other regenerative therapies, the proposed high risk/high impact studies have the potential to yield unique, rapidly translatable and safe diagnostic and therapeutic tools to improve both quality of care and prognosis of patients with breast cancer.