Pancreatic ductal adenocarcinoma (PDAC) is lethal. There is a dire need for better therapeutic targets. Cancer cells have increased demand for sugars, amino acids, and lipids and therefore up-regulate various nutrient transporters to meet this demand. In PDAC, SLC6A14 (an amino acid transporter (AAT)) is up-regulated, affecting overall patient survival. Previously we have shown using in vitro cell culture models and in vivo xenograft mouse models that pharmacological inhibition of SLC6A14 with α-methyl-l-tryptophan (α-MLT) attenuates PDAC growth. Mechanistically, blockade of SLC6A14-mediated amino acid transport with α-MLT leads to amino acid deprivation, eventually inhibiting mTORC1 signaling pathway, in tumor cells. Here, we report on the effect of Slc6a14 deletion on various parameters of PDAC in KPC mice, a model for spontaneous PDAC. Pancreatic tumors in KPC mice show evidence of Slc6a14 up-regulation. Deletion of Slc6a14 in this mouse attenuates PDAC growth, decreases the metastatic spread of the tumor, reduces ascites fluid accumulation, and improves overall survival. At the molecular level, we show lower proliferation index and reduced desmoplastic reaction following Slc6a14 deletion. Furthermore, we find that deletion of Slc6a14 does not lead to compensatory up-regulation in any of the other amino transporters. In fact, some of the AATs are actually down-regulated in response to Slc6a14 deletion, most likely related to altered mTORC1 signaling. Taken together, these results underscore the positive role SLC6A14 plays in PDAC growth and metastasis. Therefore, SLC6A14 is a viable drug target for the treatment of PDAC and also for any other cancer that overexpresses this transporter.

中文翻译：

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Slc6a14 的缺失降低了自发性胰腺癌 KPC 小鼠模型的癌症生长和转移扩散并提高了存活率

胰腺导管腺癌 (PDAC) 是致命的。迫切需要更好的治疗靶点。癌细胞对糖、氨基酸和脂质的需求增加，因此上调各种营养转运蛋白以满足这种需求。在 PDAC 中，SLC6A14（一种氨基酸转运蛋白 (AAT)）被上调，影响患者的总体存活率。以前，我们已经使用体外细胞培养模型和体内异种移植小鼠模型表明，用 α-甲基-l-色氨酸 (α-MLT) 对 SLC6A14 的药理学抑制会减弱 PDAC 的生长。从机制上讲，用 α-MLT 阻断 SLC6A14 介导的氨基酸转运会导致氨基酸剥夺，最终抑制肿瘤细胞中的 mTORC1 信号通路。在这里，我们报告了 Slc6a14 缺失对 KPC 小鼠（自发 PDAC 模型）中 PDAC 各种参数的影响。KPC 小鼠的胰腺肿瘤显示出 Slc6a14 上调的证据。该小鼠中 Slc6a14 的缺失减弱了 PDAC 的生长，减少了肿瘤的转移扩散，减少了腹水积聚，并提高了总体存活率。在分子水平上，我们在 Slc6a14 缺失后显示出较低的增殖指数和减少的促纤维增生反应。此外，我们发现 Slc6a14 的缺失不会导致任何其他氨基转运蛋白的代偿性上调。事实上，一些 AAT 实际上是响应 Slc6a14 缺失而下调的，这很可能与改变的 mTORC1 信号传导有关。总之，这些结果强调了 SLC6A14 在 PDAC 生长和转移中的积极作用。所以，