Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms
Open accessPublished version of a preprint
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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Autophagy is critical for cancer cell growth and tumorigenesis in mouse models of PDAC.
“Autophagy is critical for cancer cell growth and tumorigenesis in mouse models of PDAC207–209”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [209]
Inhibiting autophagy in cancer cells through a doxycycline-inducible dominant-negative ATG4B protein increased susceptibility to FIRINOX treatment in SPF mice compared to control cells or mSt-ATG4B cells without doxycycline treatment.
“inhibiting autophagy in cancer cells through a doxycycline-inducible dominant-negative ATG4B protein (mSt-ATG4B)29 increased the susceptibility to FIRINOX treatment in SPF mice in comparison to control cells (mSt) or mSt-ATG4B cells without doxycycline treatment (Extended Data Fig. 8m).”
From Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer (2023) · cites this paper as [29]
Autophagy is an essential metabolic program for PDAC to proliferate and thrive.
“autophagy is an essential metabolic program for PDAC to proliferate and thrive29.”
From Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer (2023) · cites this paper as [29]
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References 42 · Cited by 349
Research works printed but not linked: 1
- [25]Miller-Ocuin JL Bahary NS Singhi AD Normolle DP Lembersky B Stoller R Inhibition of Autophagy Improves Pathologic and Biomarker Response to Preoperative Gemcitabine/Nab-Paclitaxel in Potentially Resectable Pancreatic Cancer: A Phase II Randomized Controlled Trial Annals of surgical oncology 2017 24 S6 S7
- Authors
- Yang, A., Herter-Sprie, G., Zhang, H., Lin, E. Y., Biancur, D., Wang, X., Deng, J., Hai, J., Yang, S., Wong, K.-K., & Kimmelman, A. C.
- Affiliations
- Harvard University (US)
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- Corresponding author
- Wong, Kwok-Kin
- Kimmelman, Alec C.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2018-03-01
- Volume
- 8
- Issue
- 3
- Pages
- 276-287
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5835190
- OpenAlex
- W2783887386
- Cited by
- 349
- References
- 42
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 58 · 2023: 38 · 2022: 36 · 2021: 53 · 2020: 51 · 2019: 40 · 2018: 24
- FWCI
- 32.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (R01CA157490, R01CA188048, P01CA117969)
- HHS | NIH | National Institute of General Medical Sciences (NIGMS) (R01GM095567)
- American Cancer Society (ACS) (RSG-13-298-01-TBG)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- autophagy, pancreatic ductal adenocarcinoma, autophagy inhibition, tumor growth, tumor regression, cell-autonomous mechanisms, host effects, autochthonous mouse model, autophagy inhibitors, pancreatic cancer treatment
- MeSH terms
- Autophagy-Related Proteins, Animals, Autophagy, Cysteine Endopeptidases, Doxycycline, Mice, Transgenic, Neoplasms, Experimental, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal
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