Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri
{"title":"Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.","authors":"Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri","doi":"10.1158/1541-7786.MCR-24-0337","DOIUrl":null,"url":null,"abstract":"<p><p>Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction, LMI) is, emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis, but its impact on mitochondrial function has not been explored. Here, we show that in the context of high TMEM16A SCCHN, (1) patients display increased mitochondrial content, specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitates a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of lysosome-mitochondria interaction may serve as a therapeutic approach for patients with high TMEM16A expressing SCCHN.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-24-0337","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction, LMI) is, emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis, but its impact on mitochondrial function has not been explored. Here, we show that in the context of high TMEM16A SCCHN, (1) patients display increased mitochondrial content, specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitates a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of lysosome-mitochondria interaction may serve as a therapeutic approach for patients with high TMEM16A expressing SCCHN.
期刊介绍:
Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.