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2. Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

Author

Yang, Yang, Gomez, Maria, Marsh, Timothy, Poillet-Perez, Laura, Sawant, Akshada, Chen, Lei, Park, Noel R, Jackson, S RaElle, Hu, Zhixian, Alon, Noa, Liu, Chen, Debnath, Jayanta, Guan, Jun-Lin, Davidson, Shawn, Verzi, Michael, and White, Eileen

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Stem Cell Research, Digestive Diseases, Regenerative Medicine, Stem Cell Research - Nonembryonic - Non-Human, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Animals, Autophagy, Autophagy-Related Protein 5, Autophagy-Related Protein 7, Autophagy-Related Proteins, Cell Survival, Intestines, Mice, Receptor, Platelet-Derived Growth Factor alpha, Stem Cells, autophagy, intestine, stem cells, IBD, metabolism
Abstract

Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

Published
2022

3. Ribosome profiling reveals a functional role for autophagy in mRNA translational control.

Author

Goldsmith, Juliet, Marsh, Timothy, Asthana, Saurabh, Leidal, Andrew M, Suresh, Deepthisri, Olshen, Adam, and Debnath, Jayanta

Subjects
Ribosomes, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, DNA Damage, BRCA2 Protein, RNA, Messenger, Protein Biosynthesis, Gene Expression Regulation, Autophagy, Autophagy-Related Protein 12, Mechanistic Target of Rapamycin Complex 1
Abstract

Autophagy promotes protein degradation, and therefore has been proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. To date, how autophagy influences the protein synthesis landscape in mammalian cells remains unclear. Here, we utilize ribosome profiling to delineate the effects of genetic ablation of the autophagy regulator, ATG12, on translational control. In mammalian cells, genetic loss of autophagy does not impact global rates of cap dependent translation, even under starvation conditions. Instead, autophagy supports the translation of a subset of mRNAs enriched for cell cycle control and DNA damage repair. In particular, we demonstrate that autophagy enables the translation of the DNA damage repair protein BRCA2, which is functionally required to attenuate DNA damage and promote cell survival in response to PARP inhibition. Overall, our findings illuminate that autophagy impacts protein translation and shapes the protein landscape.

Published
2020

4. Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression

Author

Marsh, Timothy, Kenific, Candia M, Suresh, Deepthisri, Gonzalez, Hugo, Shamir, Eliah R, Mei, Wenbin, Tankka, Alexandra, Leidal, Andrew M, Kalavacherla, Sandhya, Woo, Kimberly, Werb, Zena, and Debnath, Jayanta

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Autophagy, Cells, Cultured, Female, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, MCF-7 Cells, Mammary Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Transcriptome, Keratin14, NBR1, Rubicon, TP63, autophagy, breast cancer, chloroquine, metastasis, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.

Published
2020

5. The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles

Author

Leidal, Andrew M, Huang, Hector H, Marsh, Timothy, Solvik, Tina, Zhang, Dachuan, Ye, Jordan, Kai, FuiBoon, Goldsmith, Juliet, Liu, Jennifer Y, Huang, Yu-Hsin, Monkkonen, Teresa, Vlahakis, Ariadne, Huang, Eric J, Goodarzi, Hani, Yu, Li, Wiita, Arun P, and Debnath, Jayanta

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Adaptor Proteins, Vesicular Transport, Animals, Autophagosomes, Autophagy, Autophagy-Related Protein 7, Autophagy-Related Proteins, Biological Transport, Biotinylation, Extracellular Vesicles, Gene Expression Profiling, Gene Expression Regulation, HEK293 Cells, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Intracellular Signaling Peptides and Proteins, Lysosomes, Matrix Attachment Region Binding Proteins, Mice, Microtubule-Associated Proteins, Nuclear Matrix-Associated Proteins, Proteomics, RAW 264.7 Cells, RNA, Small Untranslated, RNA-Binding Proteins, Receptors, Estrogen, Sphingomyelin Phosphodiesterase, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Traditionally viewed as an autodigestive pathway, autophagy also facilitates cellular secretion; however, the mechanisms underlying these processes remain unclear. Here, we demonstrate that components of the autophagy machinery specify secretion within extracellular vesicles (EVs). Using a proximity-dependent biotinylation proteomics strategy, we identify 200 putative targets of LC3-dependent secretion. This secretome consists of a highly interconnected network enriched in RNA-binding proteins (RBPs) and EV cargoes. Proteomic and RNA profiling of EVs identifies diverse RBPs and small non-coding RNAs requiring the LC3-conjugation machinery for packaging and secretion. Focusing on two RBPs, heterogeneous nuclear ribonucleoprotein K (HNRNPK) and scaffold-attachment factor B (SAFB), we demonstrate that these proteins interact with LC3 and are secreted within EVs enriched with lipidated LC3. Furthermore, their secretion requires the LC3-conjugation machinery, neutral sphingomyelinase 2 (nSMase2) and LC3-dependent recruitment of factor associated with nSMase2 activity (FAN). Hence, the LC3-conjugation pathway controls EV cargo loading and secretion.

Published
2020

7. Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

Author

Starobinets, Hanna, Ye, Jordan, Broz, Miranda, Barry, Kevin, Goldsmith, Juliet, Marsh, Timothy, Rostker, Fanya, Krummel, Matthew, and Debnath, Jayanta

Subjects
Immunization, Cancer, Rare Diseases, Orphan Drug, Vaccine Related, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antimalarials, Autophagy, Cell Line, Tumor, Female, Immunity, Cellular, Mammary Neoplasms, Experimental, Melanoma, Mice, Mice, Transgenic, T-Lymphocytes, Medical and Health Sciences, Immunology
Abstract

The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts.

Published
2016

8. How to make white people happy : a short story collection

Author

Marsh, Timothy Laurence and Dub, Rosemary

Subjects
828
Abstract

‘How to Make White People Happy’ is a creative and critical thesis that explores the nature of the journeying condition and the realities of cross-cultural immersion. The creative component is a collection of forty-three autobiographical stories that fuse elements of memoir, travelogue, satire and essay. In it, readers find docujournals about Indonesian slum life, hostile New Mexico cowboys, and star-struck pool boys who dream of fistfighting Chuck Norris. Alone in the city of Paris, a bereaved widow discovers some hard truths about travel and escapism, while on the bleak prairie barrens of Montana a grizzled recluse encounters a different kind of child’s play in an isolated barn. Readers also meet a dying Newfoundlander who dreams of an unusual cut of steak, two young lovers experimenting with the explicit in someone else’s house, and an abandoned Balinese orphan who rises to success in an elitist Anglo society. The exegesis which accompanies the collection focuses on western middle-class travel and discusses the influences and perceptions that drive it, primarily the influence of tourist media and its glorifications of travel life. Drawing from a range of scholars and writers such as Alain de Botton, James Clifford, Mark Twain, Gustave Flaubert and Charles Baudelaire, the commentary emphasizes that any alteration of our human condition occurs foremost through dynamic psychological shifts, rather than geographical ones. Other topics discussed include: belonging and displacement, the relationship between expectation and disillusionment, and aspects of travel narration, specifically humour, satire and point of view.

Published
2016

9. Ironing out VPS34 inhibition

Author

Marsh, Timothy and Debnath, Jayanta

Subjects
Biochemistry and Cell Biology, Biological Sciences, Aminopyridines, Autophagy, Cell Communication, Class III Phosphatidylinositol 3-Kinases, Humans, Intracellular Signaling Peptides and Proteins, Nuclear Receptor Coactivators, Proteins, Pyridines, Pyrimidines, Pyrimidinones, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

The class III phosphoinositide 3-kinase VPS34 regulates autophagosome formation. Three groups have developed VPS34 inhibitors and shown their utility in investigating and defining autophagic processes.

Published
2015

14. Supplementary Figure 2 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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15. Supplementary Figure 1 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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16. Data from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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19. Data from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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21. Supplementary Figure 6 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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22. Supplementary Methods, Figure Legends 1-8 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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25. Supplementary Figure 3 from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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26. Supplementary Figure 4 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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27. Supplementary Figure 5 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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28. Supplementary Table 1 from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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30. Supplementary Figure 8 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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32. Supplementary Figure 3 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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33. Supplementary Figure Legends from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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34. Supplementary Figure 2 from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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35. Supplementary Figure 7 from Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells

Author

Kuznetsov, Hanna S., primary, Marsh, Timothy, primary, Markens, Beth A., primary, Castaño, Zafira, primary, Greene-Colozzi, April, primary, Hay, Samantha A., primary, Brown, Victoria E., primary, Richardson, Andrea L., primary, Signoretti, Sabina, primary, Battinelli, Elisabeth M., primary, and McAllister, Sandra S., primary

Published
2023
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36. Supplementary Figure 1 from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Author

Alspach, Elise, primary, Flanagan, Kevin C., primary, Luo, Xianmin, primary, Ruhland, Megan K., primary, Huang, Hui, primary, Pazolli, Ermira, primary, Donlin, Maureen J., primary, Marsh, Timothy, primary, Piwnica-Worms, David, primary, Monahan, Joseph, primary, Novack, Deborah V., primary, McAllister, Sandra S., primary, and Stewart, Sheila A., primary

Published
2023
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38. To Each Their Own: Reclaiming the Japanese Otome Genre as Empowering in the West through LudoConsent

Author

Marsh, Timothy, Katayama, Kumiko, Howard, Tina N, Marsh, Timothy, Katayama, Kumiko, and Howard, Tina N

Abstract

Otome games are a genre of game that originated in Japan and are narrative-based, romance-driven games made specifically for women. Otome games have not been traditionally popular in the West, however, this has started changing. Otome games are becoming more popular in the West; this is reflected by the number of Japanese Otome games being translated to English and released in Western markets, increasing year after year. In Otome games, the player controls a female player character and pursues romance with one of the available non-player character suitors. Objections against Otome games come largely from Western feminist groups, scholars and female players who say that due to the nature of Otome games (specifically their pandering to gender stereotypes and biases, their use of the male gaze, and their romantic tropes), they are oppressive to women. This thesis will explore these criticisms further by expanding on how and why Otome games can be oppressive to women in the West and questioning whether scholars and feminists highlighting the oppressive nature of Otome games impact the choices players and developers make when making decisions in regard to the types of games they play and create. Acknowledging both cultural differences and objections to Otome game content, this thesis then explores how the individual experience with an Otome game is personal and unique (like with any game) and that these experiences differ from player to player. It is argued that Otome games, regardless of the problematic content they contain, can create positive and empowering experiences for some female players. This thesis challenges these current perceptions by re-positioning both the Otome genre of games, as well as the choice to consume such content, as empowering for the player base. [...], Thesis (PhD Doctorate), Doctor of Philosophy (PhD), Griffith Film School, Arts, Education and Law, Full Text

Published
2023

39. Regulation of breast cancer metastasis and organ homeostasis by autophagy

Author

Marsh, Timothy John

Subjects
Biology, Cellular biology, Molecular biology, Autophagy, Breast Cancer, Keratin 14, Metastasis, NBR1, Tp63
Abstract

Metastasis is the process by which tumor cells spread from the primary tumor to distant organs and form secondary tumors. In breast cancer, over 90% of cancer-related deaths are due to metastatic recurrence, which can occur even decades after surgical removal of the primary tumor. Moreover, metastatic lesions are often resistant to anti-cancer therapies effective at curbing primary tumor growth, a fact underscoring the need for a deeper understanding of the biological processes governing metastasis. In recent years, tumor cell autophagy has emerged as an attractive therapeutic target to thwart cancer progression. Autophagy (from the Greek for “self-eating”) is a highly conserved, intracellular catabolic program endowing tumor cells the ability to respond to and survive a wide variety of environmental stressors, including chemotherapies. Thus, anti-malarials, namely Hydroxychloroquine, have been repurposed as autophagy inhibitors in clinical trials for the treatment of advanced solid tumors, as they block lysosomal degradation of autophagosomal cargo. However, despite these advances in our understanding of autophagy and cancer pathogenesis, it remains unclear how autophagy inhibition impacts metastatic recurrence, the primary cause of death in breast cancer.Here, I investigate the functional consequences of tumor cell autophagy inhibition during distinct stages of breast cancer progression and metastasis. While tumor cell autophagy inhibition in the primary tumor attenuates its growth, autophagy-inhibition in disseminated tumor cells paradoxically promotes outgrowth into macro-metastases. Moreover, surgically excised autophagy-deficient primary tumors exhibited a propensity to recur locally and at metastatic sites, suggesting that autophagy inhibition promotes tumor initiating capabilities. Mechanistically, I uncover that autophagy controls metastatic outgrowth of disseminated tumor cells via degradation of the autophagy-specific substrate and cargo receptor, NBR1. Upon accumulation in autophagy-deficient cells, NBR1 elicits the acquisition of basal and stem-like traits in a subpopulation of otherwise luminal tumor cells, endowing them with an increased propensity for metastatic growth. Moreover, I demonstrate that pharmacologically enforced induction of autophagy in tumor cells elicits the autophagic degradation of NBR1 and prevents disseminated tumor cells for forming overt metastases. Taken together, this work demonstrates that autophagic degradation of NBR1 is a potential therapeutic strategy for preventing metastatic recurrence in breast cancer. Given that pharmacological autophagy inhibition will impair autophagy in all tissues, I investigate how systemic autophagy inhibition impacts organ homeostasis in cancer-free animals. I find autophagy-deficiency to induce profound perturbations to the growth and metabolic state of the animal. Autophagy-deficient animals exhibit decreases in weight and size which is underscored by decreases in adipose and lean mass as well as in bone area, mineral content and density. This general loss of tissue mass is not due to decreased nutritional consumption, suggesting that the ability to utilize nutrients is potently controlled by autophagy. Additionally, autophagy-deficiency elicits de novo beiging of adipose tissue in the mammary gland, evidenced by upregulation of UCP1, which is concomitant with loss of mature basal epithelial populations, marked by TP63 and CK14. Overall, these findings demonstrate the multi-faceted roles of autophagy in normal tissue function and cancer progression.

Published
2019

43. Atg12 Maintains Skeletal Integrity by Modulating Pro-Osteoclastogenic Signals and Chondrocyte Differentiation

Author

Tahimic, Candice, Bahl, Disha, Shirazi-Fard, Yasaman, Marsh, Timothy, Schreurs, Anne-Sofie, Rael, Victoria E, Glikbarg, Chloe, Debnath, Jayantha, and Globus, Ruth K

Subjects
Life Sciences (General)
Abstract

Weightlessness and radiation, two unique elements of space, profoundly decreases bone mass. This bone loss is attributed to increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our long-term goal is to identify signaling pathways that may be targeted to mitigate bone loss in scenarios of space exploration, radiotherapy and accidental radiation exposure. We have previously shown that exposure of MLO-Y4 osteocyte-like cells to simulated space radiation (56Fe) increased the expression of the pro-osteoclastogenic gene rankl and decreased protein levels of LC3B-II, a key player in autophagy. In this current study, we aimed to further elucidate the role of autophagy in maintaining structural integrity of the skeleton. We hypothesize that loss of autophagy in bone leads to an imbalance in pro-osteoclastogenic and pro-osteogenic signals, resulting in net bone loss. To test our hypothesis we performed global postnatal deletion of Atg12 using tamoxifeninducible Cre recombinase under the control of the CAG promoter. Six-week-old CAGCreERT2/ FloxAtg12 animals were treated daily with Tamoxifen or Vehicle (Control, oil only) for five days and euthanasia performed two weeks after the onset of treatment. Percent change in body weights (prior to treatment and at euthanasia) was not significantly different between treatment groups within the same gender. Compared to Vehicle (Control) groups, Tamoxifen (Atg12 iKO) groups showed decreased LC3B-I to II conversion and increased p62 protein levels, consistent with loss of autophagy. Quantitative PCR revealed increased expression of proosteoclastogenic cytokines mcp1 and rankl in bone and marrow respectively in male iKOs compared to male controls. Expression levels of these genes were not significantly altered in the Atg12 iKO females compared to females controls. Microcomputed tomography of tibiae revealed decreased cortical bone volume, cortical thickness and periosteal perimeter consistent with bone loss; and a longer primary spongiosa in male Atg12 iKOs display compared to male controls. These decrements were less pronounced in the female Atg12 iKOs. Cancellous bone structure was not significantly different between iKOs and controls in both genders. Histological analysis also revealed that compared to male controls, male iKOs showed a profound increase in chondrocyte column length of the growth plate with hyper-expansion of both proliferating and hypertrophic zones. Taken together, these findings indicate that autophagy plays an important role in the maintenance of bone structural integrity by mediating the production of proosteoclastogenic signals and regulating chondrocyte proliferation and differentiation.

Published
2016

49. The verse

Author

Marsh, Timothy L.

Subjects
Newfoundland and Labrador -- Description and travel, Newfoundland and Labrador -- Social aspects, Cultural identity -- Analysis, General interest
Published
2010

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