{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:33:19Z","timestamp":1781224399386,"version":"3.54.1"},"posted":{"date-parts":[[2025,1,24]]},"group-title":"Cancer Biology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Melanoma mortality is driven by the formation and growth of distant metastases. Here, we interrogated the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma. OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1\u03b1 in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain. Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.<\/jats:p>\n                <jats:sec>\n                  <jats:title>STRUCTURED ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Melanoma mortality is driven by the formation and growth of distant metastases. However, the process and pathogenesis of melanoma metastasis remain poorly understood. Here, we interrogate the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Design<\/jats:title>\n                    <jats:p>This study includes (1) new RNA-seq analysis of primary melanomas from patients characterized for distant metastasis events; (2) RNA-seq analysis and functional testing of genetic OXPHOS inhibition (PGC1\u03b1 KO) the RCAS-TVA model, which is the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors; and (3) functional experiments of genetic OXPHOS inhibition (NDUFS4 KO) in the B16-F10 and D4M-UV2 murine melanoma cell lines, including evaluation of subcutaneous, lung, and brain metastatic site dependencies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1a in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>TRANSLATIONAL RELEVANCE<\/jats:title>\n                  <jats:p>Melanoma is the most aggressive form of skin cancer. One hallmark of this disease is a high risk of distant metastasis formation. The process and pathogenesis of metastasis in this disease remain poorly understood and there is controversy regarding the role of oxidative phosphorylation (OXPHOS) in melanoma metastasis. This study incorporates RNAseq analysis of primary melanoma tumors from patients characterized for distant metastasis events, RNAseq analysis of the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors, and functional testing in multiple syngeneic models of melanoma at different tissue sites. This integrated analysis consistently demonstrates that melanoma OXPHOS promotes distant metastasis to the lungs and brain, two of the most common and clinically relevant sites of melanoma metastasis. This improved understanding of tumor OXPHOS may represent novel vulnerabilities for therapeutics development and surveillance\/preventative strategies for melanoma metastasis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.23.633049","type":"posted-content","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T23:30:11Z","timestamp":1737761411000},"source":"Crossref","is-referenced-by-count":3,"title":["Oxidative Phosphorylation (OXPHOS) Promotes the Formation and Growth of Melanoma Lung and Brain Metastases"],"prefix":"10.64898","author":[{"given":"Renato A.","family":"Guerrieri","sequence":"first","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant M.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kircher","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA"},{"name":"Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron Y.","family":"Joon","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob R.","family":"Cortez","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allie H.","family":"Grossman","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA"},{"name":"ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA"},{"name":"Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney W.","family":"Hudgens","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora A","family":"Ledesma","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Lazcano","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian YB","family":"Onana","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara G.","family":"Knighton","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swaminathan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianghua","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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Vashisht","family":"Gopal","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"McQuade","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanleng","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Haydu","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey E.","family":"Gershenwald","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Lazar","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Tetzlaff","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Departments of Pathology and Dermatology, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheri L.","family":"Holmen","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA"},{"name":"Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA"},{"name":"Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-0912","authenticated-orcid":false,"given":"Michael A.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041022414871000_2025.01.23.633049v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"2026041022414871000_2025.01.23.633049v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0000000000000538"},{"key":"2026041022414871000_2025.01.23.633049v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.13059"},{"issue":"Suppl 2","key":"2026041022414871000_2025.01.23.633049v1.4","first-page":"ii37","article-title":"Overview of the diagnosis and management of brain, spine, and meningeal metastases","volume":"75","year":"2004","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2026041022414871000_2025.01.23.633049v1.5","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21409"},{"key":"2026041022414871000_2025.01.23.633049v1.6","unstructured":"Hasanov, M. , et al., Changes In Outcomes And Factors Associated With Survival In Melanoma Patients With Brain Metastases. 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