PMID- 29443392
OWN - NLM
STAT- MEDLINE
DCOM- 20191017
LR  - 20191017
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Print)
IS  - 0022-3417 (Linking)
VI  - 245
IP  - 1
DP  - 2018 May
TI  - Spatial aspects of oncogenic signalling determine the response to combination 
      therapy in slice explants from Kras-driven lung tumours.
PG  - 101-113
LID - 10.1002/path.5059 [doi]
AB  - 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. (c) 2018 The Authors. The Journal of 
      Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of 
      Great Britain and Ireland.
CI  - (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
      on behalf of Pathological Society of Great Britain and Ireland.
FAU - Narhi, Katja
AU  - Narhi K
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Nagaraj, Ashwini S
AU  - Nagaraj AS
AUID- ORCID: 0000-0002-9048-2116
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Parri, Elina
AU  - Parri E
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Turkki, Riku
AU  - Turkki R
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - van Duijn, Petra W
AU  - van Duijn PW
AD  - Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, 
      Rotterdam, The Netherlands.
FAU - Hemmes, Annabrita
AU  - Hemmes A
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Lahtela, Jenni
AU  - Lahtela J
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Uotinen, Virva
AU  - Uotinen V
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Mayranpaa, Mikko I
AU  - Mayranpaa MI
AD  - Department of Pathology, University of Helsinki, Helsinki, Finland.
AD  - HUSLAB, Division of Pathology, Helsinki University Hospital, Helsinki, Finland.
FAU - Salmenkivi, Kaisa
AU  - Salmenkivi K
AD  - HUSLAB, Division of Pathology, Helsinki University Hospital, Helsinki, Finland.
FAU - Rasanen, Jari
AU  - Rasanen J
AD  - Heart and Lung Centre, Department of General Thoracic and Oesophageal Surgery, 
      Helsinki University Hospital, Helsinki, Finland.
FAU - Linder, Nina
AU  - Linder N
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Trapman, Jan
AU  - Trapman J
AD  - Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, 
      Rotterdam, The Netherlands.
FAU - Rannikko, Antti
AU  - Rannikko A
AD  - Department of Urology, Helsinki University Hospital, Helsinki, Finland.
FAU - Kallioniemi, Olli
AU  - Kallioniemi O
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Af Hallstrom, Taija M
AU  - Af Hallstrom TM
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Orion Corporation, Orion Pharma, Espoo, Finland.
FAU - Lundin, Johan
AU  - Lundin J
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Sommergruber, Wolfgang
AU  - Sommergruber W
AD  - Department of Lead Discovery, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, 
      Austria.
FAU - Anders, Simon
AU  - Anders S
AUID- ORCID: 0000-0003-4868-1805
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Centre for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, 
      Germany.
FAU - Verschuren, Emmy W
AU  - Verschuren EW
AUID- ORCID: 0000-0001-5771-9129
AD  - Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 
      Helsinki, Finland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180402
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (KRAS protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
EIN - J Pathol. 2019 Jan;247(1):147. PMID: 30556602
MH  - Animals
MH  - Carcinogenesis/*genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Humans
MH  - Lung Neoplasms/genetics/metabolism/*pathology
MH  - Mitogen-Activated Protein Kinases/genetics
MH  - Pancreatic Neoplasms/genetics/pathology
MH  - Proto-Oncogene Proteins p21(ras)/*genetics
MH  - Signal Transduction/*genetics
PMC - PMC5947161
OTO - NOTNLM
OT  - non-small-cell lung cancer
OT  - oncogenic signalling
OT  - precision-cut slices
OT  - prostate cancer
OT  - spatial heterogeneity
OT  - targeted therapy
EDAT- 2018/02/15 06:00
MHDA- 2019/10/18 06:00
PMCR- 2018/05/11
CRDT- 2018/02/15 06:00
PHST- 2017/09/10 00:00 [received]
PHST- 2017/12/21 00:00 [revised]
PHST- 2018/02/07 00:00 [accepted]
PHST- 2018/02/15 06:00 [pubmed]
PHST- 2019/10/18 06:00 [medline]
PHST- 2018/02/15 06:00 [entrez]
PHST- 2018/05/11 00:00 [pmc-release]
AID - PATH5059 [pii]
AID - 10.1002/path.5059 [doi]
PST - ppublish
SO  - J Pathol. 2018 May;245(1):101-113. doi: 10.1002/path.5059. Epub 2018 Apr 2.