Autophagy has been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC), and its role in promoting established tumor growth has made it a promising therapeutic target. However, due to limitations of prior mouse models as well as the lack of potent and selective autophagy inhibitors, the ability to fully assess the mechanistic basis of how autophagy supports pancreatic cancer has been limited. To test the feasibility of treating PDAC using autophagy inhibition and further our understanding of the mechanisms of protumor effects of autophagy, we developed a mouse model that allowed the acute and reversible inhibition of autophagy. We observed that autophagy inhibition causes significant tumor regression in an autochthonous mouse model of PDAC. A detailed analysis of these effects indicated that the tumor regression was likely multifactorial, involving both tumor cell–intrinsic and host effects. Thus, our study supports that autophagy inhibition in PDAC may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models.

Significance: This work demonstrates that autophagy is critical pancreatic tumor maintenance through tumor cell–intrinsic and –extrinsic mechanisms. These results have direct clinical relevance to ongoing clinical trials as well as drug-development initiatives. Cancer Discov; 8(3); 276–87. ©2018 AACR.

See related commentary by Noguera-Ortega and Amaravadi, p. 266.

This article is highlighted in the In This Issue feature, p. 253

已显示自噬在胰腺导管腺癌（PDAC）中升高，并且其在促进已建立的肿瘤生长中的作用使其成为有希望的治疗靶标。但是，由于现有小鼠模型的局限性以及缺乏有效和选择性的自噬抑制剂，因此全面评估自噬支持胰腺癌的机制基础的能力受到限制。为了测试使用自噬抑制作用来治疗PDAC的可行性以及进一步了解自噬的肿瘤作用机制，我们开发了一种小鼠模型，该模型可以急性和可逆地抑制自噬。我们观察到自噬抑制在PDAC的本地小鼠模型中导致明显的肿瘤消退。对这些影响的详细分析表明，肿瘤消退可能是多因素的，涉及肿瘤细胞内在和宿主效应。因此，我们的研究支持PDAC中的自噬抑制可能在胰腺癌的治疗中具有未来的实用性，并说明了在相关的自体模型中评估复杂的生物过程的重要性。

启示：这项工作证明自噬是通过肿瘤细胞内在和外在机制维持胰腺肿瘤的关键。这些结果与正在进行的临床试验以及药物开发计划直接相关。巨蟹座Discov; 8（3）；276–87。©2018 AACR。

参见Noguera-Ortega和Amaravadi的相关评论，第1页。266。

本文在本期功能中突出显示。253