Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance

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Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.
OriginalsprogEngelsk
Artikelnummer114409
TidsskriftCell Reports
Vol/bind43
Udgave nummer7
Antal sider24
ISSN2211-1247
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Signe Meng, Nanditha Prasad, and Christian Dalager Vaagens\u00F8, University of Copenhagen, Denmark, for excellent technical assistance; Luis A. Pardo, Max Planck Institute for Interdisciplinary Sciences, G\u00F6ttingen, Germany, for fruitful discussions and introduction to organoid culture; and Rasmus Heller and Anders Albrechtsen, University of Copenhagen, Denmark, for help with DNA-seq and genetics analyses. The study was funded by grants from the Danish Cancer Society (grant R204-A12359, to A. Sandelin and S.F.P.), the Novo Nordisk Foundation (no. NNF19OC0058262, to A. Sandelin and S.F.P.), the Carlsberg Foundation (no. CF19-0505, to A. Sandelin; no. CF20-0491, to S.F.P.), and the Danish Council for Independent Research (no. 0134-00218B, to S.F.P. and D.C.). R.I. and J.Y. were supported by the European Union (H2020-s MSCA-ITN-2018, grant no. 813834, to A. Sandelin and S.F.P.). Conceptualization: A. Sandelin and S.F.P. Supervision: A. Sandelin, S.F.P. R.A. and D.C. Experimental design: A. Sandelin, S.F.P. and D.C. Experimental work: D.C. R.I. and H.B.A. Data analysis & figure preparation: A. Stigliani, J.Y. Y.D. D.C. R.I. H.B.A. S.F.P. and A. Sandelin. Writing \u2013 original draft: A.S. and S.F.P. Writing \u2013 review & editing: S.F.P. A. Sandelin, A. Stigliani, J.Y. Y.D. D.C. R.I. and H.B.A. Funding acquisition: S.F.P. A.S. and D.C. S.F.P. is a cofounder of SOLID Therapeutics.

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© 2024 The Author(s)

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