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Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis
Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influen...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247603/ https://www.ncbi.nlm.nih.gov/pubmed/34168038 http://dx.doi.org/10.1101/gad.345629.120 |
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author | Rudnick, Jenny A. Monkkonen, Teresa Mar, Florie A. Barnes, James M. Starobinets, Hanna Goldsmith, Juliet Roy, Srirupa Bustamante Eguiguren, Sofía Weaver, Valerie M. Debnath, Jayanta |
author_facet | Rudnick, Jenny A. Monkkonen, Teresa Mar, Florie A. Barnes, James M. Starobinets, Hanna Goldsmith, Juliet Roy, Srirupa Bustamante Eguiguren, Sofía Weaver, Valerie M. Debnath, Jayanta |
author_sort | Rudnick, Jenny A. |
collection | PubMed |
description | Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia. |
format | Online Article Text |
id | pubmed-8247603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-82476032022-01-01 Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis Rudnick, Jenny A. Monkkonen, Teresa Mar, Florie A. Barnes, James M. Starobinets, Hanna Goldsmith, Juliet Roy, Srirupa Bustamante Eguiguren, Sofía Weaver, Valerie M. Debnath, Jayanta Genes Dev Research Paper Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia. Cold Spring Harbor Laboratory Press 2021-07-01 /pmc/articles/PMC8247603/ /pubmed/34168038 http://dx.doi.org/10.1101/gad.345629.120 Text en © 2021 Rudnick et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Research Paper Rudnick, Jenny A. Monkkonen, Teresa Mar, Florie A. Barnes, James M. Starobinets, Hanna Goldsmith, Juliet Roy, Srirupa Bustamante Eguiguren, Sofía Weaver, Valerie M. Debnath, Jayanta Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title | Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title_full | Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title_fullStr | Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title_full_unstemmed | Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title_short | Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
title_sort | autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247603/ https://www.ncbi.nlm.nih.gov/pubmed/34168038 http://dx.doi.org/10.1101/gad.345629.120 |
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