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| Status |
Public on Jul 02, 2024 |
| Title |
Context-dependent roles for autophagy in myeloid cells in tumor progression [Atg5_Pymt] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Autophagy is known to suppress tumor initiation by removing genotoxic stresses in normal cells. Conversely, autophagy is also known to support tumor progression by alleviating metabolic stresses in neoplastic cells. Centered on this pro-tumor role of autophagy, there have been many clinical trials to treat cancers through systemic blocking of autophagy. Such systemic inhibition affects both tumor cells and non-tumor cells, and the consequence of blocked autophagy in non-tumor cells in the context of tumor microenvironment is relatively understudied. Here, we examined the effect of autophagy-deficient myeloid cells on the progression of autophagy-competent tumors. We found that blocking autophagy only in myeloid cells modulated tumor progression markedly but such effects were context dependent. In a tumor implantation model, the growth of implanted tumor cells was substantially reduced in mice with autophagy-deficient myeloid cells; T cells infiltrated deeper into the tumors and were responsible for the reduced growth of the implanted tumor cells. In an oncogene-driven tumor induction model, however, tumors grew faster and metastasized more in mice with autophagy-deficient myeloid cells. These data demonstrate that the autophagy status of myeloid cells plays a critical role in tumor progression, promoting or suppressing tumor growth depending on the context of tumor-myeloid cell interactions. This study indicates that systemic use of autophagy inhibitors in cancer therapy may have differential effects on rates of tumor progression in patients due to effects on myeloid cells and that this warrants more targeted use of selective autophagy inhibitors in a cancer therapy in a clinical setting.
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| Overall design |
Gene expression from Atg5 WT Tumor associated macrophages (TAMs) and Atg5 KO TAMs were analyzed by RNA-seq. PyMT tumor tissues were harvested from Atg5 WT (MMTV-PyMT + Atg5flox/flox) and Atg5 KO (MMTV-PyMT + Atg5flox/flox+LysMcre) female mice in FVB/NJ background at 65 days of age. TAMs, CD11b+ F4/80+ Ly6G- Ly6C-, were isolated by FACS from the tumor tissues.
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| Web link |
https://www.biorxiv.org/content/10.1101/2024.07.12.603292v1
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| Contributor(s) |
Choi J, Hwang S |
| Citation(s) |
39071306 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| DP2 CA225208 |
Targeting by autophagy proteins for anti-tumor immunity |
UNIVERSITY OF CHICAGO |
Seungmin Hwang |
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| Submission date |
Jun 27, 2024 |
| Last update date |
Oct 01, 2024 |
| Contact name |
Seungmin "Sam" Hwang |
| Organization name |
Broad Institute of MIT and Harvard
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| Street address |
415 Main st.
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| GSM8354773 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox mouse #1 |
| GSM8354774 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox mouse #2 |
| GSM8354775 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox mouse #3 |
| GSM8354776 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox+LysMcre mouse #1 |
| GSM8354777 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox+LysMcre mouse #2 |
| GSM8354778 |
TAM from PyMT tumor spontaneously grown in Atg5flox/flox+LysMcre mouse #3 |
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| Relations |
| BioProject |
PRJNA1129012 |
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