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Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [scRNA-seq]

ABSTRACT: Dysfunctional tumor vessels promote disease progression, and improving vessel function enhances delivery of therapeutics. However, current approaches to normalize the tumor vasculature have limited efficacy. Palbociclib, an FDA-approved cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has beneficial effects on tumor and immune cells, but its impact on tumor vasculature is unknown. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle control and impaired specification, and CDK4/6i treatment promoted TEC cycle control, enabling improved tumor vascular structure and function. To gain mechanistic insight, we performed scRNAseq that showed CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, EC junctions, and pericyte recruitment, and suppressed genes regulating glycolysis and immunosuppressive signaling. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and enhanced anti-PD-1 immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE313369 | GEO | 2026/08/28

REPOSITORIES: GEO

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Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [bulkRNA-seq]

Project description:In our studies of murine mammary tumors, we found tumor ECs (TECs) exhibited disrupted cell cycle control and impaired specification, and CDK4/6i treatment promoted TEC cycle control, enabling improved tumor vascular structure and function. We identified cell cycle state-specific gene signatures by conducting bulk RNA sequencing on FACS-isolated murine Fucci2-expressing normal ECs (NECs) from healthy mammary fat pads in early and late G1. Differential gene expression analysis comparing early vs. late G1 NECs revealed the top significantly enriched genes in each phase that were used to generate cell cycle module scores that were applied to all cells in our scRNAseq datasets obtained for tumor, normal and tumor treated with CDK4/6i.

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Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

2022-02-16 | PXD023137 | Pride

CDK4/6 Inhibition Induces CD8+ T Cell Antitumor Immunity via MIF-Induced Functional Orchestration of Tumor-Associated Macrophages

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression from the G1 to S phase. Recent findings have demonstrated that CDK4/6 inhibition (CDK4/6i) enhances antitumor immunity, as evidenced by increased tumor infiltration of CD8+ T cells, though the underlying mechanism remains unclear. Our current study reveals that CDK4/6i enhances intratumoral CD8+ T cell infiltration in breast tumors through the functional reprogramming of tumor-associated macrophages (TAMs), facilitating indirect interactions between tumor cells and CD8+ T cells. Mechanistically, CDK4/6i enhances the proliferation and activation of M1 macrophages and promote the polarization of M2 to M1 macrophages via the macrophage migration inhibitory factor (MIF)-CD44/CD74 axis between tumor cells and macrophages. CDK4/6i-trained M1 TAMs increase and activate CD8+ T cells through MHC-I antigen presentation machinery. Inhibition of MIF in tumor cells or loss of MIF reverses the immunostimulatory effects of CDK4/6i on macrophages and subsequent CD8+ T cell antitumor immunity. Therefore, CDK4/6i-trained M1 TAM supernatant therapy surmounts the immunosuppressive tumor microenvironment and invokes a tumor response to low-dose PD-1 immune checkpoint blockade therapy in breast cancers.

2026-06-29 | PXD057791 | Pride

CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer

Project description:Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLS) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.

2023-10-12 | GSE234106 | GEO

RNA sequencing of luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors

Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.

2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [scRNA-seq]

Project description:Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [scRNA-seq]

| PRJNA1379337 | ENA

Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [bulkRNA-seq]

Project description:Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature [bulkRNA-seq]

| PRJNA1379649 | ENA

FOXF1 Promotes Tumor Vessel Normalization and Prevents Lung Cancer Progression through FZD4

Project description:Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific over-expression of FOXF1 normalized tumor vessels and inhibited progression of lung cancer. FOXF1-deficiency decreased Wnt/β-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/β-catenin signaling in TECs, normalized tumor vessels and inhibited progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has a promise for future therapies in NSCLC.

2024-03-09 | GSE255969 | GEO

ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer

Project description:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.

2024-11-12 | GSE281302 | GEO

NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors

Project description:Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status

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