细胞自噬在乳腺癌肺转移中的功能研究

The majority of breast cancer mortality is caused by metastatic relapse, which requires the reactivation and outgrowth of tumor cells after they have disseminated to pre-metastatic sites and undergone prolonged dormancy. Understanding the mechanisms underpinning dormancy, reactivation, and outgrowth will provide novel approaches for the prevention and treatment of breast cancer metastasis. Cancer cells face enormous stresses at various steps of the metastatic cascade. Successful colonization in target organs requires them to overcome these stresses. Recent work has demonstrated that autophagy can promote tumor growth and survival under stressful conditions. Importantly, autophagy has also been shown to be regulated by Coco/TGFβ and Collagen/DDR1/TM4SF1 signaling and involved in stem cell self-renewal. This proposal aims to study the role of autophagy and its interplay with TM4SF1 and Coco signaling in breast cancer dormancy and metastatic relapse, and the therapeutic potential of targeting autophagy for the treatment of breast cancer metastasis to lung. This proposed research will not only investigate fundamental questions about the biology of breast cancer metastasis, it will also have significant therapeutic impact---it could establish that targeting autophagy is a viable strategy for eradicating the disseminated breast cancer cells that are responsible for metastatic relapse, and that combined inhibition of autophagy and TM4SF1 or Coco can induce the death of dormant breast cancer cells and prevent their reactivation.

绝大部分乳腺癌病人的死亡是由于肿瘤转移。在此过程中需要迁移到靶器官处于静息的肿瘤细胞，变为活性增殖状态。理解这一过程的分子机制，将为治疗转移提供新方法。在转移多步骤中，肿瘤细胞会面对各式各样的胁迫，克服所有这些胁迫，才能够在靶器官中形成转移病灶。近来的研究证明，在胁迫和应激等情况下，细胞自噬能够促进肿瘤细胞的生存和生长。本申请的目标是研究细胞自噬与TM4SF1或Coco信号通路间的相互作用，以及对于乳腺癌肺转移的作用，进而检验靶向于细胞自噬作为治疗乳腺癌肺转移的可能性。本申请不仅研究转移的生物学机制，而且还有潜在的临床治疗影响---即靶向于细胞自噬，结合同时抑制TM4SF1或Coco功能，是否是阻止乳腺癌肺转移的一种有效策略。

近年来，靶向药物逐渐成为了治疗肿瘤最成功、最重要的方法之一。然而，找到合适的抗原最具挑战性，特别是特异性靶向于肿瘤干细胞或肿瘤转移起始细胞的靶向药物。我们已发表文章证明，四跨膜蛋白 TM4SF1介导了乳腺癌转移复发。我们进一步实验证明，TM4SF1可以作为肿瘤干细胞的分子标签。而且，当外源过表达TM4SF1，能够增强肿瘤细胞的干性，进而促进肿瘤生长和转移。因此，近来我们开发了靶向TM4SF1的阻断型单克隆抗体，并通过体内外实验证明，TM4SF1阻断型单克隆抗体不但能够抑制肿瘤干细胞在体外的干性能力，而且能够抑制肿瘤干细胞在体内的生长和转移。此外，为了发现抑制肿瘤干细胞自我更新的小分子化合物，我们构建了一种高通量、且简单易重复的筛选平台；并且捕获了一系列的小分子药物，验证了分子靶点。进而为将来的转化应用，以及联合用药治疗肿瘤，提供了潜在的分子靶标和可能的联合用药方式。