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Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts.
Kuiken, Hendrik J; Dhakal, Sabin; Selfors, Laura M; Friend, Chandler M; Zhang, Tian; Callari, Maurizio; Schackmann, Ron C J; Gray, G Kenneth; Crowdis, Jett; Bhang, Hyo-Eun C; Baslan, Timour; Stegmeier, Frank; Gygi, Steven P; Caldas, Carlos; Brugge, Joan S.
Afiliación
  • Kuiken HJ; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Dhakal S; Ludwig Center at Harvard, Boston, MA, 02115, USA.
  • Selfors LM; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, 1066 CX, the Netherlands.
  • Friend CM; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Zhang T; Ludwig Center at Harvard, Boston, MA, 02115, USA.
  • Callari M; Inzen Therapeutics, Cambridge, MA, 02142, USA.
  • Schackmann RCJ; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Gray GK; Ludwig Center at Harvard, Boston, MA, 02115, USA.
  • Crowdis J; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Bhang HC; Ludwig Center at Harvard, Boston, MA, 02115, USA.
  • Baslan T; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Stegmeier F; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
  • Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • Caldas C; Ludwig Center at Harvard, Boston, MA, 02115, USA.
  • Brugge JS; Merus, Utrecht, 3584 CM, the Netherlands.
Oncogene ; 41(1): 112-124, 2022 01.
Article en En | MEDLINE | ID: mdl-34703030
Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived from a single triple-negative breast cancer cell line, including copy number analysis, whole-exome and RNA sequencing, proteome analysis, and barcode analysis of clonal dynamics, as well as functional assays. The SCPs were found to have multiple unique genetic alterations and displayed significant variation in anchorage independent growth and tumor forming ability. Analyses of clonal dynamics in SCP mixtures using DNA barcode technology revealed selection for distinct clonal populations in different in vitro and in vivo environmental contexts, demonstrating that in vitro propagation of cancer cell lines using different culture conditions can contribute to the establishment of unique strains. These analyses also revealed strong enrichment of a single SCP during the development of xenograft tumors in immune-compromised mice. This SCP displayed attenuated interferon signaling in vivo and reduced sensitivity to the antiproliferative effects of type I interferons. Reduction in interferon signaling was found to provide a selective advantage within the xenograft microenvironment specifically. In concordance with the previously described role of interferon signaling as tumor suppressor, these findings suggest that similar selective pressures may be operative in human cancer and patient-derived xenograft models.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Heterogeneidad Genética / Microambiente Tumoral / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Heterogeneidad Genética / Microambiente Tumoral / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido