Centrosome linker–induced tetraploid segregation errors link rhabdoid phenotypes and lethal colorectal cancers

Andrea Remo, Erminia Manfrin, Pietro Parcesepe, Alberto Ferrarini, Hye Seung Han, Ugnius Mickys, Carmelo Laudanna, Michele Simbolo, Donatella Malanga, Duarte Mendes Oliveira, Elisabetta Baritono, Tommaso Colangelo, Lina Sabatino, Jacopo Giuliani, Enrico Molinari, Marianna Garonzi, Luciano Xumerle, Massimo Delledonne, Guido Giordano, Claudio Ghimenton & 9 others Fortunato Lonardo, Fulvio D'angelo, Federica Grillo, Luca Mastracci, Giuseppe Viglietto, Michele Ceccarelli, Vittorio Colantuoni, Aldo Scarpa, Massimo Pancione

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Centrosome anomalies contribute to tumorigenesis, but it remains unclear how they are generated in lethal cancer phenotypes. Here, it is demonstrated that human microsatellite instable (MSI) and BRAFV600E-mutant colorectal cancers with a lethal rhabdoid phenotype are characterized by inactivation of centrosomal functions. A splice site mutation that causes an unbalanced dosage of rootletin (CROCC), a centrosome linker component required for centrosome cohesion and separation at the chromosome 1p36.13 locus, resulted in abnormally shaped centrosomes in rhabdoid cells from human colon tissues. Notably, deleterious deletions at 1p36.13 were recurrent in a subgroup of BRAFV600E-mutant and microsatellite stable (MSS) rhabdoid colorectal cancers, but not in classical colorectal cancer or pediatric rhabdoid tumors. Interfering with CROCC expression in near-diploid BRAFV600E-mutant/MSI colon cancer cells disrupts bipolar mitotic spindle architecture, promotes tetraploid segregation errors, resulting in a highly aggressive rhabdoid-like phenotype in vitro. Restoring near-wild-type levels of CROCC in a metastatic model harboring 1p36.13 deletion results in correction of centrosome segregation errors and cell death, revealing a mechanism of tolerance to mitotic errors and tetraploidization promoted by deleterious 1p36.13 loss. Accordingly, cancer cells lacking 1p36.13 display far greater sensitivity to centrosome spindle pole stabilizing agents in vitro. These data shed light on a previously unknown link between centrosome cohesion defects and lethal cancer phenotypes providing new insight into pathways underlying genome instability. Implications: Mis-segregation of chromosomes is a prominent feature of chromosome instability and intratumoral heterogeneity recurrent in metastatic tumors for which the molecular basis is unknown. This study provides insight into the mechanism by which defects in rootletin, a centrosome linker component causes tetraploid segregation errors and phenotypic transition to a clinically devastating form of malignant rhabdoid tumor.

Original languageEnglish
Pages (from-to)1385-1395
Number of pages11
JournalMolecular Cancer Research
Volume16
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018
Externally publishedYes

Fingerprint

Centrosome
Tetraploidy
Colorectal Neoplasms
Phenotype
Rhabdoid Tumor
Microsatellite Repeats
Neoplasms
Spindle Poles
Chromosomal Instability
Chromosome Segregation
Spindle Apparatus
Genomic Instability
Excipients
Diploidy
Colonic Neoplasms
Colon
Carcinogenesis
Cell Death
Chromosomes
Pediatrics

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Remo, A., Manfrin, E., Parcesepe, P., Ferrarini, A., Han, H. S., Mickys, U., ... Pancione, M. (2018). Centrosome linker–induced tetraploid segregation errors link rhabdoid phenotypes and lethal colorectal cancers. Molecular Cancer Research, 16(9), 1385-1395. https://doi.org/10.1158/1541-7786.MCR-18-0062

Centrosome linker–induced tetraploid segregation errors link rhabdoid phenotypes and lethal colorectal cancers. / Remo, Andrea; Manfrin, Erminia; Parcesepe, Pietro; Ferrarini, Alberto; Han, Hye Seung; Mickys, Ugnius; Laudanna, Carmelo; Simbolo, Michele; Malanga, Donatella; Oliveira, Duarte Mendes; Baritono, Elisabetta; Colangelo, Tommaso; Sabatino, Lina; Giuliani, Jacopo; Molinari, Enrico; Garonzi, Marianna; Xumerle, Luciano; Delledonne, Massimo; Giordano, Guido; Ghimenton, Claudio; Lonardo, Fortunato; D'angelo, Fulvio; Grillo, Federica; Mastracci, Luca; Viglietto, Giuseppe; Ceccarelli, Michele; Colantuoni, Vittorio; Scarpa, Aldo; Pancione, Massimo.

In: Molecular Cancer Research, Vol. 16, No. 9, 01.09.2018, p. 1385-1395.

Research output: Contribution to journalArticle

Remo, A, Manfrin, E, Parcesepe, P, Ferrarini, A, Han, HS, Mickys, U, Laudanna, C, Simbolo, M, Malanga, D, Oliveira, DM, Baritono, E, Colangelo, T, Sabatino, L, Giuliani, J, Molinari, E, Garonzi, M, Xumerle, L, Delledonne, M, Giordano, G, Ghimenton, C, Lonardo, F, D'angelo, F, Grillo, F, Mastracci, L, Viglietto, G, Ceccarelli, M, Colantuoni, V, Scarpa, A & Pancione, M 2018, 'Centrosome linker–induced tetraploid segregation errors link rhabdoid phenotypes and lethal colorectal cancers', Molecular Cancer Research, vol. 16, no. 9, pp. 1385-1395. https://doi.org/10.1158/1541-7786.MCR-18-0062
Remo, Andrea ; Manfrin, Erminia ; Parcesepe, Pietro ; Ferrarini, Alberto ; Han, Hye Seung ; Mickys, Ugnius ; Laudanna, Carmelo ; Simbolo, Michele ; Malanga, Donatella ; Oliveira, Duarte Mendes ; Baritono, Elisabetta ; Colangelo, Tommaso ; Sabatino, Lina ; Giuliani, Jacopo ; Molinari, Enrico ; Garonzi, Marianna ; Xumerle, Luciano ; Delledonne, Massimo ; Giordano, Guido ; Ghimenton, Claudio ; Lonardo, Fortunato ; D'angelo, Fulvio ; Grillo, Federica ; Mastracci, Luca ; Viglietto, Giuseppe ; Ceccarelli, Michele ; Colantuoni, Vittorio ; Scarpa, Aldo ; Pancione, Massimo. / Centrosome linker–induced tetraploid segregation errors link rhabdoid phenotypes and lethal colorectal cancers. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 9. pp. 1385-1395.
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AU - Remo, Andrea

AU - Manfrin, Erminia

AU - Parcesepe, Pietro

AU - Ferrarini, Alberto

AU - Han, Hye Seung

AU - Mickys, Ugnius

AU - Laudanna, Carmelo

AU - Simbolo, Michele

AU - Malanga, Donatella

AU - Oliveira, Duarte Mendes

AU - Baritono, Elisabetta

AU - Colangelo, Tommaso

AU - Sabatino, Lina

AU - Giuliani, Jacopo

AU - Molinari, Enrico

AU - Garonzi, Marianna

AU - Xumerle, Luciano

AU - Delledonne, Massimo

AU - Giordano, Guido

AU - Ghimenton, Claudio

AU - Lonardo, Fortunato

AU - D'angelo, Fulvio

AU - Grillo, Federica

AU - Mastracci, Luca

AU - Viglietto, Giuseppe

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AU - Scarpa, Aldo

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