頭頸癌是全球第六大癌症。在台灣，它是男性癌症死亡的第四大原因。儘管包括手術、放療、化療和（或）靶向治療在內的多模式治療取得了進展，但仍有超過 50% 的局部晚期患者在治療後復發。晚期 HNSCC 的5年生存率仍然很低（<50%）。看似成功治療後的癌症復發和轉移是癌症患者死亡的主要原因之一，而化療後存活的耐藥性癌細胞是造成這個問題的主要原因。有許多研究探討化療抗藥性細胞，然而，在化療後存活的殘留休眠癌細胞中參與調節轉移的機制仍然很大程度上未知。我們選擇短時間藥物治療來探索化療後休眠存活癌細胞的特性。我們使用的紫杉醇劑量足以殺死超過97%的細胞，在紫杉醇處理三天後收集了存活的休眠T-S1 cells。使用細胞凋亡測定，表明與親本細胞相比，T-S1 cells耐受更高劑量的化療藥物。球體形成實驗表明，與親本細胞相比，T-S1 cells對失巢凋亡的抵抗力更強。T-S1 cells上皮間質轉化 (EMT) 標誌物的表達增加，但在體外爬行實驗不強於親本細胞。老鼠體內外滲實驗發現T-S1 cells具有更強的外滲能力，表明T-S1 cells可能需要微環境因素或細胞間溝通來激活T-S1 cells外滲能力。這一結果表明，EMT 標誌物的高表達並不一定意味著細胞更有能力外滲。我們發現T-S1 cells細胞在RNA-seq分析中主要調節ECM，而PI3在ECM的調節中最高上調表達，可能在ECM重塑中起作用。我們還發現I型干擾素途徑(type I interferon pathway)在T-S1 cells中顯著上調。I型干擾素途徑是否與ECM重塑相關將進一步檢驗。最後，我們確定了 RSPRY1，它是一種分泌蛋白，已知在臨床情況下調節癌症進展，在T-S1 cells中上調。RSPRY1在調節T-S1 cells中的作用需要進一步研究。綜上所述，我們的研究結果表明，化療後存活的殘留休眠癌細胞可能是癌症轉移後復發的罪魁禍首。

Head and neck cancer is the sixth leading cancer worldwide. In Taiwan, it is the 4th leading cause of cancer deaths among men. Although progress has been made in multimodal therapy involving surgery, radiotherapy, chemotherapy, and/or targeted therapy, over 50% of patients with locally advanced disease relapse even after treatment. The 5-year survival rate in advanced head and neck squamous cell carcinoma (HNSCC) remains poor (<50%). Cancer recurrence and metastasis after seemingly successful treatment is one of the leading causes of mortality in patients with cancer. Chemo-resistant cancer cells that survived after chemotherapy is largely responsible for this problem. There are many studies investigating chemo-resistant cells, however, the mechanism involved in the regulation of metastasis in residue dormant cancer cells that survived after chemotherapy remain largely unknown. We choose transient drug treatment to explore the details of surviving cancer cells after chemotherapy, namely, chemo-surviving cells. We collected chemo-surviving T-S1 cells after three-day-treatment of paclitaxel, using dose high enough to kill over 97% of cells. We generate T-S1 cells acquired stem-like and dormant properties. Using apoptosis assay, it was shown that T-S1 cells were tolerant to higher doses of chemotherapeutic drug compared to parental cells. Sphere formation assay revealed that T-S1 cells were more resistant to anoikis compared to parental cells. The expression of epithelial-mesenchymal transition (EMT) markers were increased in T-S1 cells while their ability to migrate in vitro is not stronger than that of parental cells. In vivo metastasis assay showed that T-S1 harbored stronger metastasis ability, indicating that T-S1 cells may require micro-environmental factors or cell-to-cell crosstalk to activate T-S1 metastatic properties. This result revealed that high expression of EMT markers does not necessarily mean that cells are more capable of metastasis. We find that T-S1 cells mainly regulate ECM in NGS analysis, and peptidase inhibitor 3 (PI3), mostly upregulated in the regulation of ECM, may plays a role in ECM remodeling. We also identify type I interferon pathway is significantly up-regulated in T-S1 cells. It would be further examed whether type I interferon pathway would be associated with ECM remodeling. At last, we identify Ring Finger And SPRY Domain Containing 1(RSPRY1), a secreted protein, is known to regulate cancer progression in clinical situation, is up-regulated in T-S1 cells. The role of RSPRY1 in the regulation of T-S1 needs further examination. Taken together, our results indicate that the residual dormant cancer cells that survived after chemotherapy may be the culprit for cancer recurrence after metastasis.

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