Dataset Information

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

ABSTRACT: Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer.

Significance

In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.

SUBMITTER: Carroll C

PROVIDER: S-EPMC10919208 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

Carroll Christopher C Manaprasertsak Auraya A Boffelli Castro Arthur A van den Bos Hilda H Spierings Diana C J DCJ Wardenaar René R Bukkuri Anuraag A Engström Niklas N Baratchart Etienne E Yang Minjun M Biloglav Andrea A Cornwallis Charlie K CK Johansson Bertil B Hagerling Catharina C Arsenian-Henriksson Marie M Paulsson Kajsa K Amend Sarah R SR Mohlin Sofie S Foijer Floris F McIntyre Alan A Pienta Kenneth J KJ Hammarlund Emma U EU

Cancer research communications 20240301 3

Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response prote ...[more]

PMID: 38385626

Similar Datasets

Project description:To induce new variation within the Escallonia genus, chromosome doubling was performed in E. rubra, E. rosea, and E. illinita, three important species within this genus of mainly evergreen woody ornamental species. Obtained tetraploids and diploid controls were analyzed for rooting capacity, leaf and flower characteristics, and plant architecture using image analysis and cold tolerance. In the present study, a breeders' collection of 23 accessions was characterized cytogenetically and described morphologically. All analyzed species and cultivars were diploid (2n = 2x = 24), with exception of E. pendula, a tetraploid. Today, breeding in Escallonia is limited to lucky finds in seedling populations and few efforts in interspecific hybridization. Three selected Escallonia species underwent an in vitro chromosome doubling with both oryzalin and trifluralin applied as either a continuous or shock treatment. The treatments successfully induced polyploids in all three species. Image analysis revealed that tetraploid E. rosea had decreased shoot length (from 3.8 to 1.3 cm), higher circularity and more dense growth habit compared to diploids. No significant changes in cold tolerance were seen. Tetraploid E. illinita did not differ in shoot length, but an increased outgrowth of axillary buds on the main axis led to denser plants. For tetraploid E. rubra, an increase in plant height (from 4.9 to 5.5 cm) was observed together with a large decrease in circularity and density due to a more polar outgrowth of branches on the main axis. E. rubra tetraploids bore larger flowers than diploids and had an increased cold tolerance (from -7.7 to -11.8°C). Leaf width and area of tetraploids increased for both E. illinita and E. rubra, while a decrease was seen in E. rosea genotypes. For all three species, the rooting capacity of the tetraploids did not differ from the diploids. We conclude that the effect of polyploidization on Escallonia was highly variable and species dependent.

Dataset Information

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

Significance

Publications

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

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