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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival
Open accessAbstract
Autophagy has been proposed to promote cell death during lumen formation in three-dimensional mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells after detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring antiapoptotic lesions.
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“Anoikis, a form of apoptosis caused by inappropriate cell/ECM interactions, has been reported in the formation of the lumen during the development of various secretory glands such as mammary and salivary glands.[20,21]”
From Autophagy, not apoptosis, plays a role in lumen formation of eccrine gland organoids (2022) · cites this paper as [21]
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Avivar‐Valderas, A., Bobrovnikova-Marjon, E. V., Diehl, J. A., Bardeesy, N. M., Debnath, J., & Aguirre‐Ghiso, J. A. (2012) · Oncogene · doi:10.1038/onc.2012.512 · Cited by 163
Self-citationDormancy and cancer stem cells: An enigma for cancer therapeutic targeting
Talukdar, S., Bhoopathi, P., Emdad, L., Das, S. K., Sarkar, D., & Fisher, P. B. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2018.12.002 · Cited by 167
Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis
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NBR1 enables autophagy-dependent focal adhesion turnover
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Autophagy and EMT in cancer and metastasis: Who controls whom?
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Extracellular matrix regulation of autophagy
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Self-citationIns(1,4,5) P 3 receptor-mediated Ca 2+ signaling and autophagy induction are interrelated
Decuypere, J.-P., Welkenhuyzen, K., Luyten, T., Ponsaerts, R., Dewaele, M., Molgó, J., Agostinis, P., Missiaen, L., De Smedt, H., Parys, J. B., et al. (2011) · Autophagy · doi:10.4161/auto.7.12.17909 · Cited by 159
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“Recent work demonstrates that TBC1D5 can shuttle between the retromer complex and LC3+ autophagosomes during starvation (Popovic et al., 2012), but the physiological functions for this RabGAP in endosomal-autophagy crosstalk have not been fully delineated.”
InfluentialSelf-citationThe role of autophagy induced by tumor microenvironment in different cells and stages of cancer
Yang, X. F., Yu, D., Yan, F., Jing, Y., Han, Z., Sun, K., Liang, L., Hou, J., & Wei, L. (2015) · Cell & Bioscience · doi:10.1186/s13578-015-0005-2 · Cited by 155
“Depletion of human ATGs, such as ATG5, ATG6 and ATG7, by si-RNA inhibits matrix detachment-induced autophagy [65].”
BackgroundGudipaty, S. A., Conner, C. M., Rosenblatt, J., & Montell, D. J. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100616-060748 · Cited by 150
“Aside from using autophagy in response to metabolic stress to promote survival and resistance to anoikis (Fung et al. 2008), many aggressive cancers have adopted differential signaling to bypass anoikis and survive in places that normal cells cannot.”
BackgroundMalignant Precursor Cells Pre-Exist in Human Breast DCIS and Require Autophagy for Survival
Espina, V. A., Mariani, B. D., Gallagher, R. I., Tran, K., Banks, S., Wiedemann, J., Huryk, H., Mueller, C., Adamo, L., Deng, J., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010240 · Cited by 146
“The second link is anoikis, the triggering of apoptotic cell death for cells that have been separated from their normal adhesion substratum [32].”
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“showed that autophagy is induced in non-transformed cells following matrix detachment which protects cells from anoikis [80].”
Self-citationIntegrins and Cell Metabolism: An Intimate Relationship Impacting Cancer
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“Several studies have noted a role for AMPK in mediating resistance to anoikis upon matrix detachment [120,215,216].”
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“Mammary epithelial cells activate macroautophagy in response to detachment to suppress anoikis.(10) Detached non-transformed cells have reduced ATP levels, and oncogenic transformation reduces energy stress through modulation of glucose uptake and reactive oxygen species.”
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Synergies in exosomes and autophagy pathways for cellular homeostasis and metastasis of tumor cells
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“Autophagy promotes resistance to anoikis, a trait that is important for the survival of tumor cells that have detached and are circulating (15, 16).”
BackgroundAntioxidant Enzymes Mediate Survival of Breast Cancer Cells Deprived of Extracellular Matrix
Davison, C. A., Durbin, S., Thau, M. R., Zellmer, V. R., Chapman, S. E., Diener, J. M., Wathen, C. A., Leevy, W. M., & Schafer, Z. T. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2482 · Cited by 124
MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells
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“Anoikis, is a form of apoptosis, triggered when cells detach from the ECM (6, 7) and the catabolic process of autophagy imparts anoikisresistance in solid tumors (29, 30).”
BackgroundCell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis
Ohsawa, S., Vaughen, J. P., & Igaki, T. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.009 · Cited by 124
“One intriguing escape route from anoikis is by activating autophagy to survive via cellular selfcannibalization (Fung et al., 2008).”
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“igenesis [53].”
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“[9] found that autophagy-protected epithelial cancer cells from anoikis which was referred to the death of cancer cell due to detachment from the extracellular matrix.”
BackgroundAutophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression
Marsh, T., Kenific, C. M., Suresh, D., Velozo, H. G., Shamir, E. R., Mei, W., Tankka, A. T., Leidal, A. M., Kalavacherla, S., Woo, K., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.01.025 · Cited by 124
“In recent years, numerous in vitro studies implicate autophagy in supporting prometastatic behavior of tumor cells such as adhesionindependent survival, metabolic adaptation, and cell invasion and motility (Fung et al., 2008; Galavotti et al., 2013; Kenific et al., 2016; Rabinowitz and White, 2010).”
BackgroundSelf-citationAutophagy, Stress, and Cancer Metabolism: What Doesn't Kill You Makes You StrongerPreprint
Mathew, R., & White, E. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2012.76.011015 · Cited by 131
“Human cancer cell lines with endogenous K-Ras mutations activate autophagy upon extracellular matrix (ECM) detachment, which protects them from detachment-induced cell death (anoikis) (Fung et al. 2008).”
BackgroundAutophagy in tumour cell death
Macintosh, R. L., & Ryan, K. M. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.05.006 · Cited by 122
Metadata
- Authors
- Fung, C., Lock, R., Gao, S., Salas, E., & Debnath, J.
- Affiliations
- University of California, San Francisco (US)
- Harvard University (US)
- *Department of Pathology and
- ORCID
- Debnath, Jayanta
- Venue
- Molecular Biology of the Cell
- Published
- 2008-03
- Volume
- 19
- Issue
- 3
- Pages
- 797-806
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2262959
- OpenAlex
- W2039403501
- Cited by
- 558
- References
- 52
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 15 · 2023: 26 · 2022: 33 · 2021: 45 · 2020: 41 · 2019: 35 · 2018: 36 · 2017: 23 · 2016: 40 · 2015: 37 · 2014: 44 · 2013: 43 · 2012: 28
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Association for Cancer Research
- National Institutes of Health
- Genentech
- University of California, San Francisco
- National Cancer Institute (K08CA098419)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- autophagy, anoikis, extracellular matrix detachment, lumen formation, epithelial morphogenesis, apoptosis, Bcl-2, ATG5, ATG7, clonogenic survival, autophagy-related genes, mammary tumor cells
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Cell Adhesion, Cell Line, Cell Survival, Dogs, Epidermal Growth Factor, Epithelial Cells, Extracellular Matrix, Fibroblasts, Humans, Microtubule-Associated Proteins, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Ubiquitin-Activating Enzymes, Mice, ErbB Receptors
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