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Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras-driven lung tumours

Authors :
Närhi, K. (Katja)
Nagaraj, A.S. (Ashwini S)
Parri, E. (Elina)
Turkki, R. (Riku)
Duijn, P.W. (Petra) van
Hemmes, A. (Annabrita)
Lahtela, J. (Jenni)
Uotinen, V. (Virva)
Mäyränpää, M.I. (Mikko I)
Salmenkivi, K. (Kaisa)
Räsänen, J. (Jari)
Linder, N. (Nina)
Trapman, J. (Hans)
Rannikko, A.S. (Antti)
Kallioniemi, O. (Olli)
Af Hällström, T.M. (Taija)
Lundin, J. (Johan)
Sommergruber, W. (Wolfgang)
Anders, S. (Simon)
Verschuren, E.W. (Emmy W.)
Närhi, K. (Katja)
Nagaraj, A.S. (Ashwini S)
Parri, E. (Elina)
Turkki, R. (Riku)
Duijn, P.W. (Petra) van
Hemmes, A. (Annabrita)
Lahtela, J. (Jenni)
Uotinen, V. (Virva)
Mäyränpää, M.I. (Mikko I)
Salmenkivi, K. (Kaisa)
Räsänen, J. (Jari)
Linder, N. (Nina)
Trapman, J. (Hans)
Rannikko, A.S. (Antti)
Kallioniemi, O. (Olli)
Af Hällström, T.M. (Taija)
Lundin, J. (Johan)
Sommergruber, W. (Wolfgang)
Anders, S. (Simon)
Verschuren, E.W. (Emmy W.)
Publication Year :
2018

Abstract

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.

Details

Database :
OAIster
Notes :
application/pdf, Journal of Pathology, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1042810069
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1002.path.5059