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Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer

ABSTRACT: Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.

OTHER RELATED OMICS DATASETS IN: PXD009442

INSTRUMENT(S): Bruker

SUBMITTER: Sara Samino

PROVIDER: MTBLS678 | MetaboLights | 2019-08-19

REPOSITORIES: MetaboLights

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Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer.

Abad Etna E García-Mayea Yoelsis Y Mir Cristina C Sebastian David D Zorzano Antonio A Potesil David D Zdrahal Zbynek Z Lyakhovich Alex A Lleonart Matilde E ME

Molecular & cellular proteomics : MCP 20181029 2

Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mit ...[more]

PMID: 30373788

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Project description:This a model from the article: A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment Fereshteh Nazari, Alexander T. Pearson, Jacques Eduardo Nor, Trachette L. Jackson. PloS Computational Biology, 2018 Jan. Abstract: Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. Author Summary: A small population of cancer stem cells that share many of the biological characteristics of normal adult stem cells are believed to initiate and sustain tumor growth for a wide variety of malignancies. Growth and survival of these cancer stem cells is highly influenced by tumor micro-environmental factors and molecular signaling initiated by cytokines and growth factors. This work focuses on quantifying the influence of IL-6, a pleiotropic cytokine secreted by a variety of cell types, on cancer stem cell self-renewal and survival. We present a mathematical model for IL-6 mediated, cancer stem cell driven tumor growth that operates at the following levels: (1) the molecular level—capturing cell surface dynamics of receptor-ligand binding and receptor activation that lead to intra-cellular signal transduction cascades; and (2) the cellular level—describing tumor growth, cellular composition, and response to treatments targeted against IL-6. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Autophagy degrades and recycles intracellular components to sustain metabolism and survival during starvation. Tumor cells upregulate and require autophagy to support their metabolism and enhance their proliferation and malignancy, and host autophagy also promotes tumor growth by providing essential tumor nutrients such as arginine in the circulation or alanine in the local tumor microenvironment. In addition to its metabolic role, autophagy regulates immune cell homeostasis and function, and suppresses inflammation, which may also play a role in cancer. Although host autophagy does not promote a T cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that in contrast to low TMB tumors, host-specific deletion of the essential autophagy gene Atg7 induces a pro-inflammatory cytokine response and limits the growth of high TMB tumors, which is rescued by T-cell depletion. Expression of immune-related genes is increased in tumors from Atg7Δ/Δ hosts in a T-cell dependent manner. Tumors from Atg7Δ/Δ hosts also have decreased T regulatory cells (Tregs), and depletion of Tregs phenocopies the reduced tumor growth observed in Atg7Δ/Δ hosts. Moreover, loss of Stimulator of interferon genes (Sting) or IFNg restores growth of high TMB tumors on Atg7Δ/Δ hosts. Finally, similar to whole-body loss of autophagy, specific loss of autophagy in the liver is sufficient to limit tumor growth. Thus, autophagy, especially in the liver, promotes tumor immune tolerance by limiting STING, T cells, and IFNg, which enables tumor growth. We have designated this: Hepatic Autophagy Immune Tolerance (HAIT). Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load, and autophagy inhibition is an effective means to promote an anti-tumor T-cell response in high TMB tumors. Genomic DNA Profiling using Agilent SureSelect Mouse All Exon kit and sequencing using Illumina NextSeq550

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