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

Autor: Wolfgang Sommergruber, Riku Turkki, Mikko I. Mäyränpää, Olli Kallioniemi, Katja Närhi, Jenni Lahtela, Virva Uotinen, Emmy W. Verschuren, Annabrita Hemmes, Taija af Hällström, Simon Anders, Antti Rannikko, Jari Räsänen, Nina Linder, Ashwini S. Nagaraj, Petra W van Duijn, Kaisa Salmenkivi, Elina Parri, Jan Trapman, Johan Lundin
Přispěvatelé: Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Research Group Verschuren Emmy, HUSLAB, Department of Pathology, Medicum, Clinicum, III kirurgian klinikka, Department of Surgery, Urologian yksikkö, Olli-Pekka Kallioniemi / Principal Investigator, Johan Edvard Lundin / Principal Investigator, HUS Heart and Lung Center, HUS Abdominal Center, Precision Systems Medicine, Lung Cancer Model Systems, Urology, Pathology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Lung Neoplasms
Carcinogenesis
medicine.disease_cause
precision‐cut slices
0302 clinical medicine
non‐small‐cell lung cancer
0303 health sciences
ORIGIN
prostate cancer
targeted therapy
Original Papers
precision-cut slices
CANCER
3. Good health
Signalling
MUTANT KRAS
030220 oncology & carcinogenesis
MOUSE LUNG
INACTIVATION
KRAS
SQUAMOUS-CELL CARCINOMA
Mitogen-Activated Protein Kinases
Lung tumours
Corrigendum
Signal Transduction
LKB1
Combination therapy
3122 Cancers
CULTURES
oncogenic signalling
Pathology and Forensic Medicine
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Cell Proliferation
030304 developmental biology
Original Paper
business.industry
spatial heterogeneity
ADENOCARCINOMA
3126 Surgery
anesthesiology
intensive care
radiology
Pancreatic Neoplasms
non-small-cell lung cancer
Cancer research
3111 Biomedicine
business
Explant culture
RAS
Zdroj: Journal of Pathology, 245(1), 101-113. John Wiley & Sons Ltd.
The Journal of Pathology
ISSN: 0022-3417
Popis: 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.
Databáze: OpenAIRE
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