Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms

Cancer Discovery - Tập 8 Số 3 - Trang 276-287 - 2018
Annan Yang1, Grit S. Herter-Sprie2, Haikuo Zhang2, Elaine Y. Lin3, Douglas E. Biancur3, Xiaoxu Wang1, Jiehui Deng2, Josephine Hai2, Shenghong Yang1, Kwok‐Kin Wong2,4, Alec C. Kimmelman1,3
11Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
22Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
33Department of Radiation Oncology, Perlmutter Cancer Center, NYU Medical School, New York, New York.
44Division of Medical Oncology, Perlmutter Cancer Center, NYU Medical School, New York, New York.

Tóm tắt

Abstract 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

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Cancer Discovery

Tập 8 Số 3

276-287

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