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Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model

BACKGROUND: Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide derived from a prime sequence that is tagged with 5 arginine aa, used to tr...

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Autores principales: Ali, Nilufar, Wolf, Cody, Kanchan, Swarna, Veerabhadraiah, Shivakumar R., Bond, Laura, Turner, Matthew W., Jorcyk, Cheryl L., Hampikian, Greg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350184/
https://www.ncbi.nlm.nih.gov/pubmed/37461536
http://dx.doi.org/10.21203/rs.3.rs-3097552/v1
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author Ali, Nilufar
Wolf, Cody
Kanchan, Swarna
Veerabhadraiah, Shivakumar R.
Bond, Laura
Turner, Matthew W.
Jorcyk, Cheryl L.
Hampikian, Greg
author_facet Ali, Nilufar
Wolf, Cody
Kanchan, Swarna
Veerabhadraiah, Shivakumar R.
Bond, Laura
Turner, Matthew W.
Jorcyk, Cheryl L.
Hampikian, Greg
author_sort Ali, Nilufar
collection PubMed
description BACKGROUND: Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide derived from a prime sequence that is tagged with 5 arginine aa, used to treat triple negative breast cancer (TNBC) in an in vivo TNBC mouse model. 9S1R is administered in trehalose (9S1R-NulloPT), which enhances solubility and exhibits some independent effects against tumor growth and is thus an important component in the drug preparation. METHOD: We examined the effect of 9S1R-NulloPT on tumor growth, metabolism, metastatic burden, necrosis, tumor immune microenvironment, and the transcriptome of aggressive mouse TNBC tumors. RESULTS: The peptide-treated mice had smaller tumors in the initial phase of the treatment, as compared to the untreated control, and reduced in vivo bioluminescence at later stages, which is indicative of metabolically inactive tumors. A decrease in ex vivo bioluminescence was also observed in the excised tumors of treated mice, but not in the secondary metastasis in the lungs. The treatment also caused changes in tumor immune microenvironment with increased infiltration of immune cells and margin inflammation. The treatment upregulated 365 genes and downregulated 710 genes in tumors compared to the untreated group. Consistent with in vitro findings in breast cancer cell lines, downregulated genes in the treated TNBC tumors include Cellular Metabolic Process Related genes (179), specifically mitochondrial genes associated with TCA cycle/oxidative phosphorylation (44), and translation machinery/ribosome biogenesis genes (45). Among upregulated genes, the Developmental Pathway (13), ECM Organization (12) and Focal Adhesion Related Pathways (7) were noteworthy. We also present data from a pilot study using a bilateral BC mouse model, which supports our findings. CONCLUSION: In conclusion, although 9S1R-NulloPT was moderate at reducing the tumor volume, it altered the tumor immune microenvironment as well as the tumor transcriptome, rendering tumors metabolically less active by downregulating the mitochondrial function and ribosome biogenesis. This corroborates previously published in vitro findings.
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spelling pubmed-103501842023-07-17 Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model Ali, Nilufar Wolf, Cody Kanchan, Swarna Veerabhadraiah, Shivakumar R. Bond, Laura Turner, Matthew W. Jorcyk, Cheryl L. Hampikian, Greg Res Sq Article BACKGROUND: Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide derived from a prime sequence that is tagged with 5 arginine aa, used to treat triple negative breast cancer (TNBC) in an in vivo TNBC mouse model. 9S1R is administered in trehalose (9S1R-NulloPT), which enhances solubility and exhibits some independent effects against tumor growth and is thus an important component in the drug preparation. METHOD: We examined the effect of 9S1R-NulloPT on tumor growth, metabolism, metastatic burden, necrosis, tumor immune microenvironment, and the transcriptome of aggressive mouse TNBC tumors. RESULTS: The peptide-treated mice had smaller tumors in the initial phase of the treatment, as compared to the untreated control, and reduced in vivo bioluminescence at later stages, which is indicative of metabolically inactive tumors. A decrease in ex vivo bioluminescence was also observed in the excised tumors of treated mice, but not in the secondary metastasis in the lungs. The treatment also caused changes in tumor immune microenvironment with increased infiltration of immune cells and margin inflammation. The treatment upregulated 365 genes and downregulated 710 genes in tumors compared to the untreated group. Consistent with in vitro findings in breast cancer cell lines, downregulated genes in the treated TNBC tumors include Cellular Metabolic Process Related genes (179), specifically mitochondrial genes associated with TCA cycle/oxidative phosphorylation (44), and translation machinery/ribosome biogenesis genes (45). Among upregulated genes, the Developmental Pathway (13), ECM Organization (12) and Focal Adhesion Related Pathways (7) were noteworthy. We also present data from a pilot study using a bilateral BC mouse model, which supports our findings. CONCLUSION: In conclusion, although 9S1R-NulloPT was moderate at reducing the tumor volume, it altered the tumor immune microenvironment as well as the tumor transcriptome, rendering tumors metabolically less active by downregulating the mitochondrial function and ribosome biogenesis. This corroborates previously published in vitro findings. American Journal Experts 2023-06-28 /pmc/articles/PMC10350184/ /pubmed/37461536 http://dx.doi.org/10.21203/rs.3.rs-3097552/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Ali, Nilufar
Wolf, Cody
Kanchan, Swarna
Veerabhadraiah, Shivakumar R.
Bond, Laura
Turner, Matthew W.
Jorcyk, Cheryl L.
Hampikian, Greg
Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title_full Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title_fullStr Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title_full_unstemmed Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title_short Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
title_sort nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350184/
https://www.ncbi.nlm.nih.gov/pubmed/37461536
http://dx.doi.org/10.21203/rs.3.rs-3097552/v1
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