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

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. 266This article is highlighted in the In This Issue feature, p. 253.

[1]  E. White,et al.  Autophagy and Tumor Metabolism. , 2017, Cell metabolism.

[2]  L. Recht,et al.  The Promise of Targeting Macrophages in Cancer Therapy , 2017, Clinical Cancer Research.

[3]  A. Thorburn,et al.  Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors , 2017, eLife.

[4]  Terje Johansen,et al.  Microenvironmental autophagy promotes tumour growth , 2017, Nature.

[5]  L. Cantley,et al.  Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion , 2016, Nature.

[6]  M. Saif,et al.  Recent advances in pancreatic cancer: updates and insights from the 2015 annual meeting of the American Society of Clinical Oncology , 2016, Therapeutic advances in gastroenterology.

[7]  E. White,et al.  Atg7 cooperates with Pten loss to drive prostate cancer tumor growth , 2016, Genes & development.

[8]  R. Amaravadi,et al.  Emerging strategies to effectively target autophagy in cancer , 2016, Oncogene.

[9]  Douglas Hanahan,et al.  Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit. , 2015, Cancer cell.

[10]  K. Ross,et al.  Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism , 2015, Nature.

[11]  L. Liotta,et al.  Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma , 2015, Annals of Surgical Oncology.

[12]  E. White,et al.  Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma. , 2015, Cancer discovery.

[13]  Q. Zhong.  Faculty Opinions recommendation of Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. , 2015 .

[14]  R. Mak,et al.  Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models , 2014, Nature Communications.

[15]  A. Kimmelman,et al.  Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status , 2014, Autophagy.

[16]  J. Meyerhardt,et al.  Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. , 2014, The oncologist.

[17]  Gerald C. Chu,et al.  Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. , 2014, Cancer discovery.

[18]  J. Bradner,et al.  Combined autophagy and proteasome inhibition , 2014, Autophagy.

[19]  A. Troxel,et al.  Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma , 2014, Autophagy.

[20]  Chang S. Chan,et al.  Autophagy is required for glucose homeostasis and lung tumor maintenance. , 2014, Cancer discovery.

[21]  Jennifer B Dennison,et al.  Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer , 2014, Molecular Cancer Therapeutics.

[22]  C. Kenific,et al.  Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. , 2014, Cancer discovery.

[23]  Amy Y. M. Au,et al.  p53 status determines the role of autophagy in pancreatic tumour development , 2013, Nature.

[24]  E. White,et al.  Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRASG12D-driven lung tumors , 2013, Autophagy.

[25]  V. Karantza,et al.  Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. , 2013, Cancer discovery.

[26]  T. Jacks,et al.  Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. , 2013, Genes & development.

[27]  Derek S. Chan,et al.  The Pancreas Cancer Microenvironment , 2012, Clinical Cancer Research.

[28]  E. White.  Deconvoluting the context-dependent role for autophagy in cancer , 2012, Nature Reviews Cancer.

[29]  A. Kimmelman,et al.  The dynamic nature of autophagy in cancer. , 2011, Genes & development.

[30]  Marc Liesa,et al.  Pancreatic cancers require autophagy for tumor growth. , 2011, Genes & development.

[31]  Johannes Zuber,et al.  A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA Interference , 2011, Cell.

[32]  T. Noda,et al.  An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. , 2008, Molecular biology of the cell.

[33]  A. Bhandoola,et al.  Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. , 2007, Cell stem cell.

[34]  G. Evan,et al.  Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. , 2007, The Journal of clinical investigation.

[35]  Rudolf Jaenisch,et al.  Efficient method to generate single‐copy transgenic mice by site‐specific integration in embryonic stem cells , 2006, Genesis.

[36]  J. Whitsett,et al.  Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction , 2005, Nucleic acids research.

[37]  S. Takeda,et al.  Interleukin-11 as a Stimulatory Factor for Bone Formation Prevents Bone Loss with Advancing Age in Mice* , 2002, The Journal of Biological Chemistry.

[38]  C. Wright,et al.  The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors , 2002, Nature Genetics.

[39]  T. Jacks,et al.  Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. , 2001, Genes & development.

[40]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

[41]  B. K. Saha.  Typing of murine major histocompatibility complex with a microsatellite in the class II Eb gene. , 1996, Journal of immunological methods.

[42]  M. Willson,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011 .