Genomic and transcriptomic profiling of whole-genome-doubled triple-negative breast cancer cell populations
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE337023 | GEO | 2026/07/05
REPOSITORIES: GEO
Similar Datasets
Project description:Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, the effects of non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, on tetraploid (4N) cancer cell physiology are less understood. Here, we show that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. We find that small size is associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.
2025-05-28 | GSE297882 | GEO
Project description:Whole genome doubling (WGD) is one of the most common genetic alterations in human cancer generally associated with poor clinical outcome, yet the underlying mechanisms have not been delineated. Here we developed an experimental model of WGD using murine mammary tumor cell lines in immunocompetent mice and found that WGD triggers immune evasion characterized by reduced infiltration of CD8+ T cells. Via comprehensive cellular and molecular characterization of WGD+ and WGD- tumors at the single cell level, we determined that WGD+ cancer cells have diminished antigen presentation due to muted response to IFN stimulation in part due to epigenetic silencing of transcriptional regulators of MHCI genes via the PRC2 complex. WGD+ tumors also have lower alpha-ketoglutarate/succinate ratio that might lead to the observed increase in histone H3 lysine 27 trimethyl levels associated with repressive chromatin. Lastly, WGD+ tumors are more responsive to anti-PD-L1 blockade and to EED inhibitors and this is associated with increased antigen presentation and CD8+ T cell infiltration. Our results have important implications for the treatment of patients with WGD+ breast cancer.
2026-03-15 | GSE274140 | GEO
Project description:Whole genome doubling (WGD) is one of the most common genetic alterations in human cancer generally associated with poor clinical outcome, yet the underlying mechanisms have not been delineated. Here we developed an experimental model of WGD using murine mammary tumor cell lines in immunocompetent mice and found that WGD triggers immune evasion characterized by reduced infiltration of CD8+ T cells. Via comprehensive cellular and molecular characterization of WGD+ and WGD- tumors at the single cell level, we determined that WGD+ cancer cells have diminished antigen presentation due to muted response to IFN stimulation in part due to epigenetic silencing of transcriptional regulators of MHCI genes via the PRC2 complex. WGD+ tumors also have lower alpha-ketoglutarate/succinate ratio that might lead to the observed increase in histone H3 lysine 27 trimethyl levels associated with repressive chromatin. Lastly, WGD+ tumors are more responsive to anti-PD-L1 blockade and to EED inhibitors and this is associated with increased antigen presentation and CD8+ T cell infiltration. Our results have important implications for the treatment of patients with WGD+ breast cancer.
2026-03-15 | GSE274160 | GEO
Project description:Whole genome doubling (WGD) is one of the most common genetic alterations in human cancer generally associated with poor clinical outcome, yet the underlying mechanisms have not been delineated. Here we developed an experimental model of WGD using murine mammary tumor cell lines in immunocompetent mice and found that WGD triggers immune evasion characterized by reduced infiltration of CD8+ T cells. Via comprehensive cellular and molecular characterization of WGD+ and WGD- tumors at the single cell level, we determined that WGD+ cancer cells have diminished antigen presentation due to muted response to IFN stimulation in part due to epigenetic silencing of transcriptional regulators of MHCI genes via the PRC2 complex. WGD+ tumors also have lower alpha-ketoglutarate/succinate ratio that might lead to the observed increase in histone H3 lysine 27 trimethyl levels associated with repressive chromatin. Lastly, WGD+ tumors are more responsive to anti-PD-L1 blockade and to EED inhibitors and this is associated with increased antigen presentation and CD8+ T cell infiltration. Our results have important implications for the treatment of patients with WGD+ breast cancer.
2026-03-15 | GSE274224 | GEO
Project description:Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and Immunotherapy (ICI: immune checkpoint inhibitor) is now a standard in stages II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors presenting a high expression of PD-L1. However, whole exome sequencing of tumors in clinical trials investigating ICI for treatment of various solid tumors other than breast cancer indicate that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors. Almost all human cells are diploid. Nevertheless, a WGD happens when regulation system maintaining the diploid status fail. The WGD+ cells are tetraploid, oncogenic and facilitate tumorigenesis. The WGD occurs in 44% of breast cancers and has been correlated to advanced cases, lower survival and higher resistance to chemotherapies and targeted therapies. Therefore it is crucial todefine the role of WGD towards the immune escape/control of TNBC and response to ICI. The first step of this work was to generate different cells line in both WGD- and WGD+ status. Using a technique of membrane homofusion of parentals cells, we obtained a WGD in three different basal murine mammary tumor cell lines (67NR, 168fARN, TA3Hauschka) and one human TNBC cell (SUM 159). The acquisition of WGD was then confirmed by flow cytometry (FACS) (DNA quantity by Hoechst staining) and karyotyping. The TA3Hauschka cell line is of particular interest since it is the only murine cell line which is diploid in parental state. By injection of WGD+ or parental DP cells in mammary fat pads of syngeneic immunocompetent strain or immunocompromised (NSG) mice, we observed a plateau of tumoral growth only for immunocompetent mice injected with WGD- cells while the WGD+ tumors escaped to spontaneous immune control. No difference of growth was seen in NSG mice between WGD- and WGD+ tumors. On tumor sections, a much more pronounced necrosis was seen in WGD- tumors comparatively to WGD+ tumors in syngeneic mice while the necrosis was mild and similar for both WGD+ and WGD- tumors in NSG mice. Immunofluorescence staining demonstrated an important neutrophilic infiltration of WGD+ while the WGD- tumors had strong T-cell lymphoid infiltrates frankly superior to the lymphoid infiltration of WGD+ tumors. These differences of infiltrates have been confirmed on digested tumors by both FACS and single cells RNA expression (scRNA) analyses. The FACS analysis also showed that the WGD+ tumors had an immunosuppressive pattern with notably higher levels of Tregs cells. To validate the hypothesis that WGD- are controlled by the infiltration of cytotoxic CD8 cells (leading to higher necrosis) while WGD+ tumors induce an immunosuppressive field, we performed an in vivo experiment investigating depletion of CD8 and neutrophils (anti-CD8 and anti-Ly6G antibodies) and a treatment by anti-PD-L1 antibodies (ICI). The treatment by isotypes antibodies confirmed the immune control of only the WGD- tumors. Anti-CD8 treatment led to an important increase in WGD- tumors growth but hadn’t any impact on WGD+ tumors while anti-Ly6G antibodies had no significative impact on WGD- and WGD+ tumors. The treatment by anti-PD-L1 antibodies was significantly more efficient to reduce the growth of WGD+ tumors than WGD- tumors. ScRNA analysis of WGD- and WGD+ untreated tumors revealed that WGD+ tumors have a significative decrease of presentation of MHCI complex. Therefore, this study highlights the potential role of biomarker of response to immune checkpoint inhibitor of whole genome doubling in TNBC.
2026-03-15 | GSE273085 | GEO
Project description:Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and Immunotherapy (ICI: immune checkpoint inhibitor) is now a standard in stages II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors presenting a high expression of PD-L1. However, whole exome sequencing of tumors in clinical trials investigating ICI for treatment of various solid tumors other than breast cancer indicate that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors. Almost all human cells are diploid. Nevertheless, a WGD happens when regulation system maintaining the diploid status fail. The WGD+ cells are tetraploid, oncogenic and facilitate tumorigenesis. The WGD occurs in 44% of breast cancers and has been correlated to advanced cases, lower survival and higher resistance to chemotherapies and targeted therapies. Therefore it is crucial todefine the role of WGD towards the immune escape/control of TNBC and response to ICI. The first step of this work was to generate different cells line in both WGD- and WGD+ status. Using a technique of membrane homofusion of parentals cells, we obtained a WGD in three different basal murine mammary tumor cell lines (67NR, 168fARN, TA3Hauschka) and one human TNBC cell (SUM 159). The acquisition of WGD was then confirmed by flow cytometry (FACS) (DNA quantity by Hoechst staining) and karyotyping. The TA3Hauschka cell line is of particular interest since it is the only murine cell line which is diploid in parental state. By injection of WGD+ or parental DP cells in mammary fat pads of syngeneic immunocompetent strain or immunocompromised (NSG) mice, we observed a plateau of tumoral growth only for immunocompetent mice injected with WGD- cells while the WGD+ tumors escaped to spontaneous immune control. No difference of growth was seen in NSG mice between WGD- and WGD+ tumors. On tumor sections, a much more pronounced necrosis was seen in WGD- tumors comparatively to WGD+ tumors in syngeneic mice while the necrosis was mild and similar for both WGD+ and WGD- tumors in NSG mice. Immunofluorescence staining demonstrated an important neutrophilic infiltration of WGD+ while the WGD- tumors had strong T-cell lymphoid infiltrates frankly superior to the lymphoid infiltration of WGD+ tumors. These differences of infiltrates have been confirmed on digested tumors by both FACS and single cells RNA expression (scRNA) analyses. The FACS analysis also showed that the WGD+ tumors had an immunosuppressive pattern with notably higher levels of Tregs cells. To validate the hypothesis that WGD- are controlled by the infiltration of cytotoxic CD8 cells (leading to higher necrosis) while WGD+ tumors induce an immunosuppressive field, we performed an in vivo experiment investigating depletion of CD8 and neutrophils (anti-CD8 and anti-Ly6G antibodies) and a treatment by anti-PD-L1 antibodies (ICI). The treatment by isotypes antibodies confirmed the immune control of only the WGD- tumors. Anti-CD8 treatment led to an important increase in WGD- tumors growth but hadn’t any impact on WGD+ tumors while anti-Ly6G antibodies had no significative impact on WGD- and WGD+ tumors. The treatment by anti-PD-L1 antibodies was significantly more efficient to reduce the growth of WGD+ tumors than WGD- tumors. ScRNA analysis of WGD- and WGD+ untreated tumors revealed that WGD+ tumors have a significative decrease of presentation of MHCI complex. Therefore, this study highlights the potential role of biomarker of response to immune checkpoint inhibitor of whole genome doubling in TNBC.
2026-03-15 | GSE273031 | GEO
Project description:Whole genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies. However, the 3D organization of the chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here, we show that in p53 deficient cells WGD induces loss of chromatin segregation (LCS), characterized by reduced segregation between short and long chromosomes, A and B sub-compartments, and adjacent chromatin domains. LCS is driven by downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primed genomic regions for sub-compartment repositioning in WGD cells, which resulted in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Importantly, sub-compartment repositioning events were largely independent of chromosomal alterations, indicating that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, suggesting that chromatin evolution is a hallmark of WGD-driven cancer.
2023-01-12 | GSE222387 | GEO
Project description:Whole genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies. However, the 3D organization of the chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here, we show that in p53 deficient cells WGD induces loss of chromatin segregation (LCS), characterized by reduced segregation between short and long chromosomes, A and B sub-compartments, and adjacent chromatin domains. LCS is driven by downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primed genomic regions for sub-compartment repositioning in WGD cells, which resulted in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Importantly, sub-compartment repositioning events were largely independent of chromosomal alterations, indicating that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, suggesting that chromatin evolution is a hallmark of WGD-driven cancer.
2023-01-12 | GSE222386 | GEO
Project description:Whole genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies. However, the 3D organization of the chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here, we show that in p53 deficient cells WGD induces loss of chromatin segregation (LCS), characterized by reduced segregation between short and long chromosomes, A and B sub-compartments, and adjacent chromatin domains. LCS is driven by downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primed genomic regions for sub-compartment repositioning in WGD cells, which resulted in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Importantly, sub-compartment repositioning events were largely independent of chromosomal alterations, indicating that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, suggesting that chromatin evolution is a hallmark of WGD-driven cancer.
2023-01-12 | GSE222385 | GEO
Project description:Whole genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies. However, the 3D organization of the chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here, we show that in p53 deficient cells WGD induces loss of chromatin segregation (LCS), characterized by reduced segregation between short and long chromosomes, A and B sub-compartments, and adjacent chromatin domains. LCS is driven by downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primed genomic regions for sub-compartment repositioning in WGD cells, which resulted in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Importantly, sub-compartment repositioning events were largely independent of chromosomal alterations, indicating that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, suggesting that chromatin evolution is a hallmark of WGD-driven cancer.
2023-01-12 | GSE222389 | GEO