2018-04-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647502摘要：經過幾世紀與癌症的征戰，病患的存活率雖僅些微的改善。然而，努力的過程累積的知識讓我們逐漸 明瞭，癌症不是單一疾病，而是一種複雜環境交互作用下的詭譎多變的疾病。現在明白癌症的多變異 質性不僅僅存在於不同病人之間，甚至在同一病人的同一腫瘤組織中，亦存在複雜的變異性。腫瘤中 的癌細胞會隨著生長擴展，乃至環境變化，而有族群演化變異發生。導致染色體不穩定、癌幹細胞的 多變異特性、及腫瘤內的動態變異，造成腫瘤的演化和對其抗藥性、腫瘤復發、和轉移，具關鍵影響 力。而這也是對抗癌症遇到最難解決的問題1,2。但是，解析這複雜演化過程的詳細分子機制是困難的; 並且，腫瘤微環境改變對癌幹性的影響及腫瘤演化壓力之角色也未明。為進一步研究演化中不同癌細 胞族群中癌幹性、基因突變、表基因變異、和表觀異質特性在抵抗癌細胞走向滅亡，我們這個“BeFIT” 團隊將利用液體檢體(liquid biopsy)(包括：循環癌細胞和惡質胸水液中癌幹細胞)和病人衍生模式 (PDX)(包括：癌幹細胞/癌纖維母細胞共培養条統和PDX-NSG小鼠模式)為研究主軸，使用基因體分 析平台執行此整合型計畫，緊密結合並深入分析腫瘤內功能性與基因異質性，對腫瘤微環境和癌幹細 胞變異性之影響，及癌細胞對微環境變化壓力所產生的複雜表觀變異度。包括，促進血管新生分化、 基因修補能力、EMT變化、和抗藥性。此計畫將有助於發展以腫瘤幹細胞為基礎之診斷、預後評估、 和治療方式，以克服腫瘤復發與變異性，也將提供精準化醫療莫大助益。<br> Abstract: After decades of fight against cancer, the mortality of patients has only slightly changed; yet the efforts allowed understanding that a cancer is not a uniform mass of similar cells but a complex ecosystem of highly plastic and different cancer cells living in symbiosis with stroma cells. It is clear now that cancer is heterogenous not only from patient to patient but also within the tumor. Intratumor history resembles to clonal evolution with clear impact of tumor expansion and microenvironmental changing. The drivers of chromosome instability, plasticity of cancer stem cells (CSCs) and dynamic intratumoral heterogeneity plays a critical role in tumour evolution and strongly impact on drug-resistance, tumor recurrence and metastasis, which are unmet for anti-cancer therapy1,2. The molecular mechanisms underlying such evolution are difficult to dissect; moreover, how the microenvironment changes may affect the cancer cell stemness and could directly drive tumoral evolution is at present unclear. To better understand the contribution of cancer stemness, genetic mutations, epigenetic variations, and phenotypic heterogeneity of the populations to resistance to cancer cell extinction, the “BeFIT team” propose to use liquid biopsy (circulating tumor cells, CTC and CSCs from pleural effusion, PE) and patient-derived models (lung CSCs/CAFs culturing system and patient-derived xenograft PDX-NSG mice), to perform an integrative project with genome-wide analysis to characterize in-depth the intratumor functional heterogeneity and to investigate the tight links between microenvironment and CSCs plasticity, which contributes to the complexity of heterogeneity and different phenotypic abilities on promoting angiogenesis, DNA repair, EMT, and drug-resistance or under environmental stresses. This should allow proposing alternative anti-CSC-based diagnostic, prognostic, and therapeutic approaches devoted to overcome tumor relapse/recurrence, heterogeneity; and will benefit for precision medicine.