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1.
Autophagy ; : 1-7, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38984617

ABSTRACT

Macroautophagy/autophagy is increasingly implicated in a variety of diseases, making it an attractive therapeutic target. However, many aspects of autophagy are not fully understood and its impact on many diseases remains debatable and context-specific. The lack of systematic and dynamic measurements in these cases is a key reason for this ambiguity. In recent years, Loos et al. 2014 and Beesabathuni et al. 2022 developed methods to quantitatively measure autophagy holistically. In this commentary, we pose some of the unresolved biological questions regarding autophagy and consider how quantitative measurements may address them. While the applications are ever-expanding, we provide specific use cases in cancer, virus infection, and mechanistic screening. We address how the rate measurements themselves are central to developing cancer therapies and present ways in which these tools can be leveraged to dissect the complexities of virus-autophagy interactions. Screening methods can be combined with rate measurements to mechanistically decipher the labyrinth of autophagy regulation in cancer and virus infection. Taken together, these approaches have the potential to illuminate the underlying mechanisms of various diseases.Abbreviation MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; R1: rate of autophagosome formation; R2: rate of autophagosome-lysosome fusion; R3: rate of autolysosome turnover.

2.
Cell Death Dis ; 14(9): 620, 2023 09 21.
Article in English | MEDLINE | ID: mdl-37735513

ABSTRACT

Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ~10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients' mutations would improve patients' outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.


Subject(s)
Autophagic Cell Death , Pancreatic Neoplasms , Animals , Humans , Mice , Autophagy/genetics , BRCA2 Protein/genetics , Pancreas , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms
3.
bioRxiv ; 2023 May 31.
Article in English | MEDLINE | ID: mdl-37398312

ABSTRACT

Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ∼10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways ( e.g., BRCA2 ). Personalized medicine approaches tailored toward patients' mutations would improve patients' outcome. To identify novel vulnerabilities of BRCA2 -deficient pancreatic cancer, we generated isogenic Brca2 -deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2 -deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2 -deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2 -deficient pancreatic cancer.

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