Plasticity within aldehyde dehydrogenase-positive cells determines prostate cancer radiosensitivity

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

Tumor heterogeneity and cellular plasticity are key determinants of tumor progression, metastatic spread, and therapy response driven by the cancer stem cell (CSC) population. Within the current study, we analyzed irradiation-induced plasticity within the aldehyde dehydrogenase (ALDH)-positive (ALDH +) population in prostate cancer. The radiosensitivity of xenograft tumors derived from ALDH + and ALDH-negative (ALDH -) cells was determined with local tumor control analyses and demonstrated different dose-response profiles, time to relapse, and focal adhesion signaling. The transcriptional heterogeneity was analyzed in pools of 10 DU145 and PC3 cells with multiplex gene expression analyses and illustrated a higher degree of heterogeneity within the ALDH + population that even increases upon irradiation in comparison with ALDH - cells. Phenotypic conversion and clonal competition were analyzed with fluorescence protein-labeled cells to distinguish cellular origins in competitive three-dimensional cultures and xenograft tumors. We found that the ALDH + population out-competes ALDH - cells and drives tumor growth, in particular upon irradiation. The observed dynamics of the cellular state compositions between ALDH + and ALDH - cells in vivo before and after tumor irradiation was reproduced by a probabilistic Markov compartment model that incorporates cellular plasticity, clonal competition, and phenotype-specific radiosensitivities. Transcriptional analyses indicate that the cellular conversion from ALDH - into ALDH + cells within xenograft tumors under therapeutic pressure was partially mediated through induction of the transcriptional repressor SNAI2. In summary, irradiation-induced cellular conversion events are present in xenograft tumors derived from prostate cancer cells and may be responsible for radiotherapy failure. Implications: The increase of ALDH + cells with stem-like features in prostate xenograft tumors after local irradiation represents a putative cellular escape mechanism inducing tumor radioresistance.

Details

Original languageEnglish
Pages (from-to)794-809
Number of pages16
JournalMolecular cancer research : MCR
Volume20
Issue number5
Early online date8 Feb 2022
Publication statusPublished - May 2022
Peer-reviewedYes

External IDs

Scopus 85129996764
WOS 000795904800001
Mendeley 5f9652ce-e2ce-38b2-84b9-1f630fccc15d
unpaywall 10.1158/1541-7786.mcr-21-0806

Keywords

Sustainable Development Goals

Keywords

  • Aldehyde Dehydrogenase/genetics, Humans, Male, Neoplasm Recurrence, Local, PC-3 Cells, Prostatic Neoplasms/genetics, Radiation Tolerance

Library keywords