Signaling Pathways that Determine Ewings Sarcoma Outcome

描述（由申请人提供）：尤文氏肉瘤家族肿瘤（ESFT）包含一个特征性易位，该易位将22号染色体上的EWS基因连接到位于11号染色体t（11;22）上的ets家族基因FLI 1。这种新的转录本被翻译成EWS/FLI 1融合蛋白，其作为致癌转录因子发挥作用。ESFT转化的另一个关键组成部分是胰岛素样生长因子（IGF）信号系统。IGF I型受体（IGF-IR）是成纤维细胞的EWS/FLI 1转化所必需的。胰岛素受体底物-1（IRS-1）是胰岛素样生长因子受体（IGF-IR）的关键底物，受酪氨酸磷酸化和去磷酸化调节。EWS/FLI 1转化与IRS-1酪氨酸磷酸化的基础减少有关;到目前为止，负责这一点的磷酸酶尚未发现。我们已经确定了一种蛋白酪氨酸磷酸酶（PTP）PTPL 1（又名PTP-BAS，人PTP 1 E，PTPN 13，后来的FAP-1），我们认为它可能负责EWS/FLI 1和IGF-IR信号之间的联系。因此，我们假设EWS/FLI 1融合蛋白通过诱导PTPL 1表达而发挥癌基因的功能。我们进一步假设PTPL 1提示ESFT中的信号平衡有利于肿瘤细胞存活和转化。除了IGF-IR，PTPL 1已被报道调节其他关键ESFT信号通路，包括Fas和p75 NTR。我们的具体目标是（i）通过评估PTPL 1水平降低的ESFT克隆的生长、存活和肿瘤发生，确定PTPL 1如何促成ESFT恶性表型，（ii）确定相关的PTPL 1临床途径，以及ESFT患者肿瘤中的PTPL 1途径特征是否影响对治疗的临床反应和总生存期（训练集，n=100，验证集n>100），和（iii）建立ESFT细胞模型中EWS/FLI 1对PTPL 1调节的性质。我们正在热情地追求磷酸酶PTPL 1如何调节ESFT生物学，作为我们目前IGF-I研究的逻辑延伸。我们在初步数据中描述的一个更重要的发现是，PTPL 1的减少严重减少了软琼脂中的ESFT菌落形成。PTPL 1是IGF-IR和Fas通路的新型调节剂。显然，如果PTPL 1被证实是一种支持性癌蛋白，并确定了PTPL 1调节的途径，那么患有许多依赖IGF-IR信号传导的其他肿瘤（包括乳腺癌）的患者可能会从我们的发现中受益。

DESCRIPTION (provided by applicant): The Ewing's sarcoma family of tumors (ESFTs) contains a characteristic translocation that joins the EWS gene on chromosome 22 to an ets family gene, FLI1, located on chromosome 11, t(11;22). This novel transcript is translated to become the EWS/FLI1 fusion protein, which functions as an oncogenic transcription factor. Another key component of transformation in ESFT is the insulin-like growth factor (IGF) signaling system. The IGF type I receptor (IGF-IR) is required for EWS/FLI1 transformation of fibroblasts. Insulin-Receptor Substrate-1 (IRS-1), the key substrate of IGF-IR is regulated by tyrosine phosphorylation and dephosphorylation. EWS/FLI1 transformation is associated with a basal reduction in tyrosine phosphorylation of IRS-1; until now, the phosphatase responsible for this has eluded discovery. We have identified a protein tyrosine phosphatase (PTP) PTPL1 (aka, PTP-BAS, human PTP1E, PTPN13, and later FAP-1) that we believe could be responsible for the connection between EWS/FLI1 and IGF-IR signaling. We therefore hypothesize that the EWS/FLI1 fusion protein functions as an oncogene by inducing PTPL1 expression. We further hypothesize that PTPL1 tips the balance of signaling in ESFT to favor tumor cell survival and transformation. In addition to IGF-IR, PTPL1 has been reported to modulate other key ESFT signaling pathways including Fas and p75NTR. Our specific aims will (i) identify how PTPL1 contributes to the ESFT malignant phenotype by evaluating growth, survival and tumorigenesis in ESFT clones with reduced PTPL1 levels, (ii) determine relevant PTPL1 clinical pathways and if PTPL1 pathway signatures in ESFT patient tumors affects clinical response to therapy and overall survival (training set, n=100, validation set n>100), and (iii) establish the nature of PTPL1 regulation by EWS/FLI1 in ESFT cell models. We are enthusiastically pursuing how the phosphatase PTPL1 regulates ESFT biology as the logical extension of our current IGF-I studies. One of the more important findings we describe in our Preliminary Data is that reduction of PTPL1 severely reduces ESFT colony formation in soft-agar. PTPL1 is a novel regulator of IGF-IR and Fas pathways. Clearly, if PTPL1 is validated as a supportive oncoprotein and the pathways modulated by PTPL1 are identified, patients with many other tumors that rely on IGF-IR signaling including breast carcinoma could benefit from our findings.