Your browser doesn't support javascript.
loading
Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras-driven lung tumours.
Närhi, Katja; Nagaraj, Ashwini S; Parri, Elina; Turkki, Riku; van Duijn, Petra W; Hemmes, Annabrita; Lahtela, Jenni; Uotinen, Virva; Mäyränpää, Mikko I; Salmenkivi, Kaisa; Räsänen, Jari; Linder, Nina; Trapman, Jan; Rannikko, Antti; Kallioniemi, Olli; Af Hällström, Taija M; Lundin, Johan; Sommergruber, Wolfgang; Anders, Simon; Verschuren, Emmy W.
Afiliación
  • Närhi K; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Nagaraj AS; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Parri E; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Turkki R; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • van Duijn PW; Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Hemmes A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Lahtela J; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Uotinen V; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Mäyränpää MI; Department of Pathology, University of Helsinki, Helsinki, Finland.
  • Salmenkivi K; HUSLAB, Division of Pathology, Helsinki University Hospital, Helsinki, Finland.
  • Räsänen J; HUSLAB, Division of Pathology, Helsinki University Hospital, Helsinki, Finland.
  • Linder N; Heart and Lung Centre, Department of General Thoracic and Oesophageal Surgery, Helsinki University Hospital, Helsinki, Finland.
  • Trapman J; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Rannikko A; Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Kallioniemi O; Department of Urology, Helsinki University Hospital, Helsinki, Finland.
  • Af Hällström TM; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Lundin J; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Sommergruber W; Orion Corporation, Orion Pharma, Espoo, Finland.
  • Anders S; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Verschuren EW; Department of Lead Discovery, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria.
J Pathol ; 245(1): 101-113, 2018 05.
Article en En | MEDLINE | ID: mdl-29443392
A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision-cut slices from Kras-driven non-small-cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen-activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short-term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3-kinase-mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology-associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Proto-Oncogénicas p21(ras) / Carcinogénesis / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Pathol Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Proto-Oncogénicas p21(ras) / Carcinogénesis / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Pathol Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido