Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

Michala G. Rolver; Juan Camacho-Roda; Yifan Dai; Mette Flinck; Renata Ialchina; Julie Hindkær; Rigmor T. Dyhr; August N. Bodilsen; Nanditha S. Prasad; Jonathan Baldan; Jiayi Yao; Albin Sandelin; Luis Arnes; Stine F. Pedersen

doi:10.1016/j.isci.2025.111956

Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

Michala G. Rolver, Juan Camacho-Roda, Yifan Dai, Mette Flinck, Renata Ialchina, Julie Hindkær, Rigmor T. Dyhr, August N. Bodilsen, Nanditha S. Prasad, Jonathan Baldan, Jiayi Yao, Albin Sandelin^*, Luis Arnes, Stine F. Pedersen

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

Originalsprog	Engelsk
Artikelnummer	111956
Tidsskrift	iScience
Vol/bind	28
Udgave nummer	3
Antal sider	17
ISSN	2589-0042
DOI	https://doi.org/10.1016/j.isci.2025.111956
Status	Udgivet - 2025

Bibliografisk note

Funding Information:
We gratefully acknowledge the excellent technical assistance of Tanja Larsen and Frida J. Birkbak, and contributions to early experiments by Eliana Alves, Muthulakshmi Ponniah, Josephine S. Kapel, Lukas K. Laursen, Anne B. Olsen, and Naiyee R. Toiviainen. We are grateful to Irina Korshunova and Konstantin Khodosevich at the BRIC single cell genomics facility for excellent guidance and technical assistance. This research was funded by Independent Research Fund Denmark ( #0135-00139B S.F.P.), the Danish Cancer Society ( #R204-A12359 , A.S. and S.F.P.) and an Elite PhD scholarship from the Department of Biology , UCPH and the Novo Nordisk Foundation ( #NNF19OC0058262 , A.S. and S.F.P.). L.A. is supported by core funding of the Biotech Research and Innovation Center , the Danish Cancer Society ( R302-A17481 and R322-A17.350 ), The Novo Nordisk Foundation ( NNF21OC0070884 ) and THE INNOVATION FUND (Eurostars 2807 ). The Novo Nordisk Foundation Center for Stem Cell Biology was supported by Novo Nordisk Foundation grants NNF17CC0027852 .

Funding Information:
We gratefully acknowledge the excellent technical assistance of Tanja Larsen and Frida J. Birkbak, and contributions to early experiments by Eliana Alves, Muthulakshmi Ponniah, Josephine S. Kapel, Lukas K. Laursen, Anne B. Olsen, and Naiyee R. Toiviainen. We are grateful to Irina Korshunova and Konstantin Khodosevich at the BRIC single cell genomics facility for excellent guidance and technical assistance. This research was funded by Independent Research Fund Denmark (#0135-00139B, S.F.P.), the Danish Cancer Society (#R204-A12359, A.S. and S.F.P.), an Elite PhD scholarship from the Department of Biology, UCPH (M.R.), and the Novo Nordisk Foundation (#NNF19OC0058262, A.S. and S.F.P.). L.A. is supported by core funding of the Biotech Research and Innovation Center, the Danish Cancer Society (R302-A17481 and R322-A17.350), and the Novo Nordisk Foundation (NNF21OC0070884). The Novo Nordisk Foundation Center for Stem Cell Biology was supported by Novo Nordisk Foundation grant NNF17CC0027852.

Publisher Copyright:
© 2025 The Author(s)

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10.1016/j.isci.2025.111956Licens: CC BY-NC

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Citationsformater

Rolver, M. G., Camacho-Roda, J., Dai, Y., Flinck, M., Ialchina, R., Hindkær, J., Dyhr, R. T., Bodilsen, A. N., Prasad, N. S., Baldan, J., Yao, J., Sandelin, A., Arnes, L., & Pedersen, S. F. (2025). Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis. iScience, 28(3), Artikel 111956. https://doi.org/10.1016/j.isci.2025.111956

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title = "Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis",

abstract = "The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.",

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T1 - Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

AU - Rolver, Michala G.

AU - Camacho-Roda, Juan

AU - Dai, Yifan

AU - Flinck, Mette

AU - Ialchina, Renata

AU - Hindkær, Julie

AU - Dyhr, Rigmor T.

AU - Bodilsen, August N.

AU - Prasad, Nanditha S.

AU - Baldan, Jonathan

AU - Yao, Jiayi

AU - Sandelin, Albin

AU - Arnes, Luis

AU - Pedersen, Stine F.

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N2 - The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

AB - The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

KW - Cancer

KW - Cell biology

KW - Microenvironment

U2 - 10.1016/j.isci.2025.111956

DO - 10.1016/j.isci.2025.111956

M3 - Journal article

AN - SCOPUS:85218257828

SN - 2589-0042

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