Cited by 558Autophagy in Disease and TherapyCell death mechanisms and regulationUbiquitin and proteasome pathways

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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

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Fung, Christopher, Lock, Rebecca, Gao, Sizhen, Salas, Eduardo, Debnath, Jayanta·2008·Molecular Biology of the Cell

DOI 10.1091/mbc.e07-10-1092PMC PMC2262959

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Abstract

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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Background
Autophagy in Thyroid Cancer: Present Knowledge and Future Perspectives
Netea-Maier, R. T., Klück, V., Plantinga, T. S., & Smit, J. W. A. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00022 · Cited by 40
“In addition, it helps preventing anoikis (cell death after the cell has been detached from its extracellular matrix) and therefore promoting survival of cells that have been detached form their extracellular matrix (98).”
Background
Sodium molybdate inhibits the growth of ovarian cancer cells via inducing both ferroptosis and apoptosis
Mao, G., Xin, D., Wang, Q., & Lai, D. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.02.023 · Cited by 40
Inhibition of autophagy; an opportunity for the treatment of cancer resistance
Tonkin-Reeves, A., Giuliani, C. M., & Price, J. T. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1177440 · Cited by 41
“Furthermore, autophagy has been shown to support the cellular changes observed in the aggressive phenotypes such as the epithelial to mesenchymal transition (Fung et al., 2008).”
Background
Rab17-mediated recycling endosomes contribute to autophagosome formation in response to Group AStreptococcusinvasion
Haobam, B., Nozawa, T., Minowa‐Nozawa, A., Tanaka, M., Oda, S., Watanabe, T., Aikawa, C., Maruyama, F., & Nakagawa, I. (2014) · Cellular Microbiology · doi:10.1111/cmi.12329 · Cited by 38
“The Rab17 dominant-negative mutant (Rab17 N132I) and constitutively active mutant (Rab17 Q77L) were constructed by introducing point mutations using a PrimeSTAR Mutagenesis Basal Kit (Takara) and the following primer pairs: Rab17 NI-forward, 5′-GTGGGCATCAAGACGGACCTCAGCCAG-3′ and Rab17 NI-reverse, 5′-CGTCTTGATGCCCACCAG…”
MethodInfluential
Non-enzymatic dissociation of human mesenchymal stromal cells improves chemokine-dependent migration and maintains immunosuppressive function
Garg, A., Houlihan, D. D., Aldridge, V., Suresh, S., Li, K. K., King, A., Sutaria, R., Fear, J., Bhogal, R. H., Lalor, P. F., et al. (2014) · Cytotherapy · doi:10.1016/j.jcyt.2013.10.003 · Cited by 38
SPIB promotes anoikis resistance via elevated autolysosomal process in lung cancer cells
Zhang, H., Wang, G., Zhou, R., Li, X., Sun, Y., Li, Y., Du, W., Yan, X., Yang, J., Chang, X., et al. (2020) · FEBS Journal · doi:10.1111/febs.15272 · Cited by 38
Organoid models in gynaecological oncology research
Semertzidou, A., Brosens, J. J., McNeish, I. A., & Kyrgiou, M. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102103 · Cited by 38
The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding
Kuramoto, K., Kim, Y.-J., Hong, J. H., & He, C. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109184 · Cited by 40
“Retrovirus production and infection— GP2–293 cells were transfected with pCMV-VSV-G and pBABEpuro GFP-LC3 (Addgene plasmid #22405) (Fung et al., 2008) plasmids using lipofectamine 3000 transfection reagents.”
Glycans in autophagy, endocytosis and lysosomal functions
Reggiori, F., Gabius, H., Aureli, M., Römer, W., Sonnino, S., & Eskelinen, E. (2021) · Glycoconjugate Journal · doi:10.1007/s10719-021-10007-x · Cited by 37
Autophagy: Mechanisms, regulation, and its role in tumorigenesis
Parkhitko, A. A., Favorova, O. O., & Henske, E. P. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913040044 · Cited by 39
Lipin‐1 determines lung cancer cell survival and chemotherapy sensitivity by regulation of endoplasmic reticulum homeostasis and autophagy
Fan, X., Weng, Y., Bai, Y., Wang, Z., Wang, S., Zhu, J., & Zhang, F. (2018) · Cancer Medicine · doi:10.1002/cam4.1483 · Cited by 38
“The original GFPLC3 (#22405) and mRFP- GFPLC3 (#22418) expression plasmids were ordered from Addgene [9].”
Method
The non-receptor tyrosine kinase Ack1 regulates activated EGFR fate by inducing trafficking to the p62/NBR1 pre-autophagosome
Jones, S., Cunningham, D. L., Rappoport, J. Z., & Heath, J. K. (2014) · Journal of Cell Science · doi:10.1242/jcs.136895 · Cited by 36
“…autophagy takes place at the basal levels within the cell, there are various stimuli that have been shown to induce autophagy, in particular withdrawal of growth factors (Wang and Levine, 2010; Mizushima et al., 2011), for example, deprivation of EGF in mammary epithelial cells (Fung et al., 2008).”
Background
Insights into the role of senescence in tumor dormancy: mechanisms and applications
DeLuca, V. J., & Saleh, T. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10082-6 · Cited by 37
“For example, autophagy induction in dormant cells is thought to facilitate their survival against anoikis [121] or apoptosis [122], which is well aligned with the classical cytoprotective function of autophagy.”
Background
Integration of Autophagy and Anoikis Resistance in Solid Tumors
Yang, J., Zheng, Z., Yan, X., Li, X., Liu, Z., & Ma, Z. (2013) · The Anatomical Record · doi:10.1002/ar.22769 · Cited by 37
“More importantly, autophagy can function as an important way to adapt to outer stresses, such as the extracellular matrix (ECM) detachment and starvation, by maintaining cellular homeostasis (Fung et al., 2008; Shang et al., 2011).”
BackgroundInfluential
Role and regulation of autophagy in the development of acinar structures formed by bovine BME-UV1 mammary epithelial cells
Sobolewska, A., Motyl, T., & Gajewska, M. (2011) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.06.007 · Cited by 37
Autophagy Is Indispensable for the Self‐Renewal and Quiescence of Ovarian Cancer Spheroid Cells with Stem Cell‐Like Properties
Wang, Q., Bu, S., Xin, D., Li, B., Wang, L., & Lai, D. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7010472 · Cited by 39
“Our results were consistent with the previous reports that extracellular matrix detachment can induce autophagy [27, 28].”
Result
The Autophagic Route of E-Cadherin and Cell Adhesion Molecules in Cancer Progression
Santarosa, M., & Maestro, R. (2021) · Cancers · doi:10.3390/cancers13246328 · Cited by 39
“Moreover, autophagy is activated as a protection mechanism to preserve cells from anoikis, a form of programmed cell death typically triggered in anchorage-dependent cells upon detachment from the extracellular matrix [180,181].”
Background
Soluble ECM promotes organotypic formation in lung alveolar model
Valdoz, J. C., Franks, N. A., Cribbs, C. G., Jacobs, D. J., Dodson, E. L., Knight, C. J., Poulson, P. D., Garfield, S. R., Johnson, B. C., Hemeyer, B. M., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121464 · Cited by 37
Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts
Chiarelli, N., Carini, G., Zoppi, N., Ritelli, M., & Colombi, M. (2019) · PLOS ONE · doi:10.1371/journal.pone.0211647 · Cited by 35
Chapter 4 Assessing Metabolic Stress and Autophagy Status in Epithelial Tumors
Mathew, R., Karantza‐Wadsworth, V., & White, E. (2009) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)04004-4 · Cited by 37
Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model
Twomey, J. D., & Zhang, B. (2019) · Cancers · doi:10.3390/cancers11010094 · Cited by 35
“It is well documented that matrix detachment increases cellular stress to trigger autophagy in cancer cells [16,17].”
Background
Metastatic Melanoma Cells Rely on Sestrin2 to Acquire Anoikis Resistance via Detoxifying Intracellular ROS
Zhu, G., Xu, P., Guo, S., Yi, X., Wang, H., Yang, Y., Liu, L., Shi, Q., Gao, T., & Li, C. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.07.720 · Cited by 35
The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis
Yuan, T., Annamalai, K., Naik, S., Lupše, B., Geravandi, S., Pal, A., Dobrowolski, A., Ghawali, J., Ruhlandt, M., Gorrepati, K. D. D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25145-x · Cited by 40
Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth
Chen, C. G., & Iozzo, R. V. (2022) · Open Biology · doi:10.1098/rsob.210304 · Cited by 34
Altered extracellular mRNA communication in postpartum depression is associated with decreased autophagy
Osborne, L. M., Payne, J. L., Sherer, M. L., & Sabunciyan, S. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01794-2 · Cited by 34
Inhibition of p21 activates Akt kinase to trigger ROS-induced autophagy and impacts on tumor growth rate
Maheshwari, M., Yadav, N., Hasanain, M., Pandey, P. K., Sahai, R., Choyal, K., Singh, A., Nengroo, M. A., Saini, K. K., Kumar, D., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05486-1 · Cited by 35
“No. 22405; created by Dr. Jayanta Debnath), [15] pMRX-IP-GFP-LC3-RFP-LC3 Δ G (Ref.”
Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1
Suzuki, J., Nakajima, W., Suzuki, H., Asano, Y., & Tanaka, N. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.12.037 · Cited by 35
Circular RNA ubiquitin-associated protein 2 enhances autophagy and promotes colorectal cancer progression and metastasis via miR-582-5p/FOXO1 signaling
Chen, F., Guo, L., Di, J., Li, M., Dong, D., & Pei, D. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.07.017 · Cited by 34
Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis
Burton, L. J., Rivera, M., Hawsawi, O., Zou, J., Hudson, T., Wang, G., Zhang, Q., Cubano, L. A., Boukli, N. M., & Odero-Marah, V. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164115 · Cited by 35
Primary differentiated respiratory epithelial cells respond to apical measles virus infection by shedding multinucleated giant cells
Lin, W.-H. W., Tsay, A. J., Lalime, E. N., Pekosz, A. S., & Griffin, D. E. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013264118 · Cited by 33
“In brief, respiratory tracts were obtained at necropsy from two male (60, 62) and two female (61, 69) healthy rhesus macaques (Macaca mulatta) obtained from Harlan Laboratories after completion of a study of measles vaccination (11).”
BackgroundMethod
Bone Metastatic Breast Cancer: Advances in Cell Signaling and Autophagy Related Mechanisms
Othman, A. H., Winogradzki, M., Lee, L., Tandon, M., Blank, A. T., & Pratap, J. (2021) · Cancers · doi:10.3390/cancers13174310 · Cited by 32
“Recent reports have demonstrated that induction of autophagy served a role in helping cells resist anoikis [71,75].”
Background
Remodeling of ER–plasma membrane contact sites but not STIM1 phosphorylation inhibits Ca 2+ influx in mitosis
Yu, F., Hubrack, S., Chakraborty, S., Sun, L., Alcantara-Adap, E., Kulkarni, R., Billing, A. M., Graumann, J., Taylor, C. W., & Machaca, K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821399116 · Cited by 33
“To generate GFP-LC3 stable HEK293 cells, cells were infected with retrovirus expressing GFP-LC3 (22405; Addgene) (68) and then, enriched for the GFP+ population (BD FACSAria II).”
MethodInfluential
Recent Advances in the Role of Autophagy in Endocrine-Dependent Tumors
Komarla, A., Dufresne, S., & Towers, C. G. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad001 · Cited by 35
Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding
Shaw, P., Bhowmik, A. D., Pillai, M. S. G., Robbins, N., Dwivedi, S. K. D., & Rao, G. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217750 · Cited by 36
The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance
Jia, H., Wei, J., Zheng, W., & Li, Z. Y. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06595-z · Cited by 33
“Throughout acini formation, autophagy protects mammary epithelial cells from anoikis, a type of cell death triggered by a lack of extracellular matrix interaction, in healthy breast development [27].”
Simultaneous Detection of Autophagy and Epithelial to Mesenchymal Transition in the Non-small Cell Lung Cancer Cells
Alizadeh, J., Shojaei, S., Sepanjnia, A., Hashemi, M. M., Eftekharpour, E., & Ghavami, S. (2017) · Methods in molecular biology · doi:10.1007/7651_2017_84 · Cited by 33
Autophagy and Its Relationship to Epithelial to Mesenchymal Transition: When Autophagy Inhibition for Cancer Therapy Turns Counterproductive
Rojas-Sánchez, G., Cotzomi-Ortega, I., Pazos-Salazar, N. G., Reyes‐Leyva, J., & Maycotte, P. (2019) · Biology · doi:10.3390/biology8040071 · Cited by 32
“One of the first links between autophagy and the invasion process was the discovery that autophagy allows epithelial cells to survive anoikis [26].”
Background
Stress signaling and the shaping of the mammary tissue in development and cancer
Avivar‐Valderas, A., Wen, H. C., & Aguirre‐Ghiso, J. A. (2014) · Oncogene · doi:10.1038/onc.2013.554 · Cited by 34
Survival of Exfoliated Epithelial Cells: A Delicate Balance between Anoikis and Apoptosis
Kaeffer, B. (2011) · BioMed Research International · doi:10.1155/2011/534139 · Cited by 36
“In three-dimensional epithelial cell cultures, both autophagy and apoptosis are observed during lumen formation [8, 9].”
BackgroundInfluential
Autophagic regulation in steroid hormone-responsive systems
Park, J., Shin, H., Song, H., & Lim, H. J. (2016) · Steroids · doi:10.1016/j.steroids.2016.09.011 · Cited by 32
“MECs detached from the matrix during lumen formation [28].”
Background
PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration
Morani, F., Phadngam, S., Follo, C., Titone, R., Thongrakard, V., Galetto, A., Alabiso, O., & Isidoro, C. (2014) · Genes & Cancer · doi:10.18632/genesandcancer.21 · Cited by 34
“In addition, autophagy and glycolysis are also involved in the ‘epithelial-tomesenchymal’ transition phenomenon that precedes the metastasization[5-7].”
Background
SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes
Choi, Y. K., Choi, Y., Choi, Y., Yun, Y. J., Lee, K. M., Lee, K., Yoo, H., Shin, Y. C., & Ko, S. (2016) · Oncotarget · doi:10.18632/oncotarget.11393 · Cited by 30
“Moreover, autophagy regulates distant metastases of cancer cells [14, 15].”

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
Publisher: American Society for Cell Biology (ASCB)
Published: 2008-03
Volume: 19
Issue: 3
Pages: 797-806
ISSN: 1059-1524 (ISSN-L)
1939-4586
DOI: 10.1091/mbc.e07-10-1092
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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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

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