N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma
High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of expression and transcriptional signature across human cancer...
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creator | Miranda, Alex Pattnaik, Swetansu Hamilton, Phineas T Fuss, Monica Alvaro Kalaria, Shreena Laumont, Céline M Smazynski, Julian Mesa, Monica Banville, Allyson Jiang, Xinpei Jenkins, Russell Cañadas, Israel Nelson, Brad H |
description | High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of
expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic
transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors. |
doi_str_mv | 10.1126/sciadv.adj5428 |
format | Article |
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expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic
transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adj5428</identifier><identifier>PMID: 38748789</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Biomedicine and Life Sciences ; Cancer ; Cell Line, Tumor ; Cystadenocarcinoma, Serous - genetics ; Cystadenocarcinoma, Serous - immunology ; Cystadenocarcinoma, Serous - metabolism ; Cystadenocarcinoma, Serous - pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity, Innate - genetics ; Immunology ; Interferon Type I - metabolism ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; N-Myc Proto-Oncogene Protein - genetics ; N-Myc Proto-Oncogene Protein - metabolism ; Neoplasm Grading ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; SciAdv r-articles ; Signal Transduction</subject><ispartof>Science advances, 2024-05, Vol.10 (20), p.eadj5428</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c346t-142d937161500617bd666c2bb41e1e458db7fec12e1c472056276544ad868a83</cites><orcidid>0000-0003-3598-7733 ; 0000-0002-3086-5326 ; 0000-0001-6110-2148 ; 0000-0002-9289-4157 ; 0000-0001-6474-711X ; 0000-0003-2358-7580 ; 0009-0003-5391-7285 ; 0009-0006-5586-3462 ; 0000-0002-9067-4054 ; 0000-0002-4445-5539</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095474/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095474/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38748789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miranda, Alex</creatorcontrib><creatorcontrib>Pattnaik, Swetansu</creatorcontrib><creatorcontrib>Hamilton, Phineas T</creatorcontrib><creatorcontrib>Fuss, Monica Alvaro</creatorcontrib><creatorcontrib>Kalaria, Shreena</creatorcontrib><creatorcontrib>Laumont, Céline M</creatorcontrib><creatorcontrib>Smazynski, Julian</creatorcontrib><creatorcontrib>Mesa, Monica</creatorcontrib><creatorcontrib>Banville, Allyson</creatorcontrib><creatorcontrib>Jiang, Xinpei</creatorcontrib><creatorcontrib>Jenkins, Russell</creatorcontrib><creatorcontrib>Cañadas, Israel</creatorcontrib><creatorcontrib>Nelson, Brad H</creatorcontrib><title>N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of
expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic
transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Biomedicine and Life Sciences</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cystadenocarcinoma, Serous - genetics</subject><subject>Cystadenocarcinoma, Serous - immunology</subject><subject>Cystadenocarcinoma, Serous - metabolism</subject><subject>Cystadenocarcinoma, Serous - pathology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunity, Innate - genetics</subject><subject>Immunology</subject><subject>Interferon Type I - metabolism</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>N-Myc Proto-Oncogene Protein - genetics</subject><subject>N-Myc Proto-Oncogene Protein - metabolism</subject><subject>Neoplasm Grading</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>SciAdv r-articles</subject><subject>Signal Transduction</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUbtOwzAUtRCIVqUrI8rIkmI7fmVCqOIlFVi6MFk3jpu6SpxiJ5X4e4JaqjLd17nnPg5C1wTPCKHiLhoH5W4G5YYzqs7QmGaSp5QzdX7ij9A0xg3GmDAhOMkv0ShTkimp8jFavKdvn_PENVtwISbOe-jsEDa9t0l0lYfa-WrIJ2tXrdMqQDnkbWj7mLQ7CA58YiAY59sGrtDFCupopwc7Qcunx-X8JV18PL_OHxapyZjoUsJomWeSCMIxFkQWpRDC0KJgxBLLuCoLubKGUEsMkxRzQaXgjEGphAKVTdD9nnbbF40tjfVdgFpvg2sgfOsWnP5f8W6tq3anCcE5Z5INDLcHhtB-9TZ2unHR2LoGb4fLdIY5VzlTnA_Q2R5qQhtjsKvjHIL1rwp6r4I-qDA03Jxud4T__Tz7AcMahRo</recordid><startdate>20240517</startdate><enddate>20240517</enddate><creator>Miranda, Alex</creator><creator>Pattnaik, Swetansu</creator><creator>Hamilton, Phineas T</creator><creator>Fuss, Monica Alvaro</creator><creator>Kalaria, Shreena</creator><creator>Laumont, Céline M</creator><creator>Smazynski, Julian</creator><creator>Mesa, Monica</creator><creator>Banville, Allyson</creator><creator>Jiang, Xinpei</creator><creator>Jenkins, Russell</creator><creator>Cañadas, Israel</creator><creator>Nelson, Brad H</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3598-7733</orcidid><orcidid>https://orcid.org/0000-0002-3086-5326</orcidid><orcidid>https://orcid.org/0000-0001-6110-2148</orcidid><orcidid>https://orcid.org/0000-0002-9289-4157</orcidid><orcidid>https://orcid.org/0000-0001-6474-711X</orcidid><orcidid>https://orcid.org/0000-0003-2358-7580</orcidid><orcidid>https://orcid.org/0009-0003-5391-7285</orcidid><orcidid>https://orcid.org/0009-0006-5586-3462</orcidid><orcidid>https://orcid.org/0000-0002-9067-4054</orcidid><orcidid>https://orcid.org/0000-0002-4445-5539</orcidid></search><sort><creationdate>20240517</creationdate><title>N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma</title><author>Miranda, Alex ; Pattnaik, Swetansu ; Hamilton, Phineas T ; Fuss, Monica Alvaro ; Kalaria, Shreena ; Laumont, Céline M ; Smazynski, Julian ; Mesa, Monica ; Banville, Allyson ; Jiang, Xinpei ; Jenkins, Russell ; Cañadas, Israel ; Nelson, Brad H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c346t-142d937161500617bd666c2bb41e1e458db7fec12e1c472056276544ad868a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Biomedicine and Life Sciences</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cystadenocarcinoma, Serous - genetics</topic><topic>Cystadenocarcinoma, Serous - immunology</topic><topic>Cystadenocarcinoma, Serous - metabolism</topic><topic>Cystadenocarcinoma, Serous - pathology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunity, Innate - genetics</topic><topic>Immunology</topic><topic>Interferon Type I - metabolism</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>N-Myc Proto-Oncogene Protein - genetics</topic><topic>N-Myc Proto-Oncogene Protein - metabolism</topic><topic>Neoplasm Grading</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>SciAdv r-articles</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miranda, Alex</creatorcontrib><creatorcontrib>Pattnaik, Swetansu</creatorcontrib><creatorcontrib>Hamilton, Phineas T</creatorcontrib><creatorcontrib>Fuss, Monica Alvaro</creatorcontrib><creatorcontrib>Kalaria, Shreena</creatorcontrib><creatorcontrib>Laumont, Céline M</creatorcontrib><creatorcontrib>Smazynski, Julian</creatorcontrib><creatorcontrib>Mesa, Monica</creatorcontrib><creatorcontrib>Banville, Allyson</creatorcontrib><creatorcontrib>Jiang, Xinpei</creatorcontrib><creatorcontrib>Jenkins, Russell</creatorcontrib><creatorcontrib>Cañadas, Israel</creatorcontrib><creatorcontrib>Nelson, Brad H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miranda, Alex</au><au>Pattnaik, Swetansu</au><au>Hamilton, Phineas T</au><au>Fuss, Monica Alvaro</au><au>Kalaria, Shreena</au><au>Laumont, Céline M</au><au>Smazynski, Julian</au><au>Mesa, Monica</au><au>Banville, Allyson</au><au>Jiang, Xinpei</au><au>Jenkins, Russell</au><au>Cañadas, Israel</au><au>Nelson, Brad H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2024-05-17</date><risdate>2024</risdate><volume>10</volume><issue>20</issue><spage>eadj5428</spage><pages>eadj5428-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of
expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic
transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>38748789</pmid><doi>10.1126/sciadv.adj5428</doi><orcidid>https://orcid.org/0000-0003-3598-7733</orcidid><orcidid>https://orcid.org/0000-0002-3086-5326</orcidid><orcidid>https://orcid.org/0000-0001-6110-2148</orcidid><orcidid>https://orcid.org/0000-0002-9289-4157</orcidid><orcidid>https://orcid.org/0000-0001-6474-711X</orcidid><orcidid>https://orcid.org/0000-0003-2358-7580</orcidid><orcidid>https://orcid.org/0009-0003-5391-7285</orcidid><orcidid>https://orcid.org/0009-0006-5586-3462</orcidid><orcidid>https://orcid.org/0000-0002-9067-4054</orcidid><orcidid>https://orcid.org/0000-0002-4445-5539</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Biomedicine and Life Sciences Cancer Cell Line, Tumor Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - immunology Cystadenocarcinoma, Serous - metabolism Cystadenocarcinoma, Serous - pathology Female Gene Expression Regulation, Neoplastic Humans Immunity, Innate - genetics Immunology Interferon Type I - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism N-Myc Proto-Oncogene Protein - genetics N-Myc Proto-Oncogene Protein - metabolism Neoplasm Grading Ovarian Neoplasms - genetics Ovarian Neoplasms - immunology Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism SciAdv r-articles Signal Transduction |
title | N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma |
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