title: Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.
abstract: Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.
authors.affiliation: 1] Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil [2] Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: E T
authors.initials: ET
authors.lastname: Costa
authors.affiliation: 1] Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil [2] Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: G F
authors.initials: GF
authors.lastname: Barnabé
authors.affiliation: Ludwig Institute for Cancer Research (LICR), University of California, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Departamento de Biologia Geral (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: A A M
authors.initials: AA
authors.lastname: Dias
authors.affiliation: Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: T R
authors.initials: TR
authors.lastname: Machado
authors.affiliation: 1] Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil [2] Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: P F
authors.initials: PF
authors.lastname: Asprino
authors.affiliation: Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: F P
authors.initials: FP
authors.lastname: Cavalher
authors.affiliation: Centro Internacional de Pesquisa, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: E N
authors.initials: EN
authors.lastname: Ferreira
authors.affiliation: Ludwig Institute for Cancer Research (LICR), University of California, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Del Mar Inda
authors.affiliation: Departamento de Bioquímica (IQ), Universidade de São Paulo, São Paulo, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: Nagai
authors.affiliation: Departamento de Bioquímica (IQ), Universidade de São Paulo, São Paulo, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Malnic
authors.affiliation: 1] Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil [2] Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Duarte
authors.affiliation: Departamento de Urologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: K R M
authors.initials: KR
authors.lastname: Leite
authors.affiliation: Departamento de Mastologia, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: A C S D
authors.initials: AC
authors.lastname: de Barros
authors.affiliation: Centro Internacional de Pesquisa, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: D M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Departamento de Urologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Chammas
authors.affiliation: 1] Departamento de Bioquímica (IQ), Universidade de São Paulo, São Paulo, Brazil [2] Instituto Butantan, São Paulo, Brazil.
authors.forename: H A
authors.initials: HA
authors.lastname: Armelin
authors.affiliation: Ludwig Institute for Cancer Research (LICR), University of California, San Diego, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cavenee
authors.affiliation: Ludwig Institute for Cancer Research (LICR), University of California, San Diego, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Furnari
authors.affiliation: 1] Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil [2] Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil.
authors.forename: A A
authors.initials: AA
authors.lastname: Camargo
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide / Q000378:metabolism*; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D016326:Extracellular Matrix Proteins; C488167:LGI4 protein, human; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D051722:ADAM Proteins; C114633:ADAM23 protein, human