An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer
Abstract Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-53999-w |
| _version_ | 1797274574365130752 |
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| author | Mauricio Jacobo Jacobo Hayley J. Donnella Sushil Sobti Swati Kaushik Andrei Goga Sourav Bandyopadhyay |
| author_facet | Mauricio Jacobo Jacobo Hayley J. Donnella Sushil Sobti Swati Kaushik Andrei Goga Sourav Bandyopadhyay |
| author_sort | Mauricio Jacobo Jacobo |
| collection | DOAJ |
| description | Abstract Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance. |
| first_indexed | 2024-03-07T15:00:20Z |
| format | Article |
| id | doaj.art-54547d28190b4392a930f8ef09f1e6a6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:00:20Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-54547d28190b4392a930f8ef09f1e6a62024-03-05T19:09:29ZengNature PortfolioScientific Reports2045-23222024-02-0114111510.1038/s41598-024-53999-wAn inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancerMauricio Jacobo Jacobo0Hayley J. Donnella1Sushil Sobti2Swati Kaushik3Andrei Goga4Sourav Bandyopadhyay5Department of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Cell & Tissue Biology, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoAbstract Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance.https://doi.org/10.1038/s41598-024-53999-w |
| spellingShingle | Mauricio Jacobo Jacobo Hayley J. Donnella Sushil Sobti Swati Kaushik Andrei Goga Sourav Bandyopadhyay An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer Scientific Reports |
| title | An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| title_full | An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| title_fullStr | An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| title_full_unstemmed | An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| title_short | An inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| title_sort | inflamed tumor cell subpopulation promotes chemotherapy resistance in triple negative breast cancer |
| url | https://doi.org/10.1038/s41598-024-53999-w |
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