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1.
Br J Cancer ; 130(6): 908-924, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38238426

RESUMEN

BACKGROUND: Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, the tumour cell subpopulations and transcriptional regulators governing these processes remained unknown. METHODS: We used single-cell transcriptomics to decipher the tumour cell subpopulations stimulated by GPx2 KD in the PyMT mammary tumour and paired pulmonary metastases. We analyzed the EMT spectrum across the various tumour cell clusters using pseudotime trajectory analysis and elucidated the transcriptional and metabolic regulation of the hybrid EMT state. RESULTS: Integration of single-cell transcriptomics between the PyMT/GPx2 KD primary tumour and paired lung metastases unraveled a basal/mesenchymal-like cluster and several luminal-like clusters spanning an EMT spectrum. Interestingly, the luminal clusters at the primary tumour gained mesenchymal gene expression, resulting in epithelial/mesenchymal subpopulations fueled by oxidative phosphorylation (OXPHOS) and glycolysis. By contrast, at distant metastasis, the basal/mesenchymal-like cluster gained luminal and mesenchymal gene expression, resulting in a hybrid subpopulation using OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated in all hybrid clusters, implying a role in regulating partial EMT and MET at primary and distant sites, respectively. Importantly, these effects were reversed by HIF1α loss or GPx2 gain of function, resulting in metastasis suppression. CONCLUSIONS: Collectively, these results underscored a dramatic effect of redox signaling on p63 activation by HIF1α, underlying phenotypic and metabolic plasticity leading to mammary tumour metastasis.


Asunto(s)
Neoplasias de la Mama , Neoplasias Pulmonares , Neoplasias Mamarias Animales , Neoplasias Primarias Secundarias , Animales , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Reprogramación Metabólica , Transición Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Oxidación-Reducción , Línea Celular Tumoral , Metástasis de la Neoplasia
2.
NPJ Breast Cancer ; 10(1): 39, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834621

RESUMEN

The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

3.
Sci Rep ; 14(1): 488, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177639

RESUMEN

Network properties account for the complex relationship between genes, making it easier to identify complex patterns in their interactions. In this work, we leveraged these network properties for dual purposes. First, we clustered pediatric sarcoma tumors using network information flow as a similarity metric, computed by the Wasserstein distance. We demonstrate that this approach yields the best concordance with histological subtypes, validated against three state-of-the-art methods. Second, to identify molecular targets that would be missed by more conventional methods of analysis, we applied a novel unsupervised method to cluster gene interactomes represented as networks in pediatric sarcoma. RNA-Seq data were mapped to protein-level interactomes to construct weighted networks that were then subjected to a non-Euclidean, multi-scale geometric approach centered on a discrete notion of curvature. This provides a measure of the functional association among genes in the context of their connectivity. In confirmation of the validity of this method, hierarchical clustering revealed the characteristic EWSR1-FLI1 fusion in Ewing sarcoma. Furthermore, assessing the effects of in silico edge perturbations and simulated gene knockouts as quantified by changes in curvature, we found non-trivial gene associations not previously identified.


Asunto(s)
Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Niño , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma de Ewing/patología , Proteína EWS de Unión a ARN/metabolismo , Neoplasias de los Tejidos Blandos/genética , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteína Proto-Oncogénica c-fli-1/genética , Línea Celular Tumoral
4.
iScience ; 27(2): 108880, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38333710

RESUMEN

Local cryoablation can engender systemic immune activation/anticancer responses in tumors otherwise resistant to immune checkpoint blockade (ICB). We evaluated the safety/tolerability of preoperative cryoablation plus ipilimumab and nivolumab in 5 early-stage/resectable breast cancers. The primary endpoint was met when all 5 patients underwent standard-of-care primary breast surgery undelayedly. Three patients developed transient hyperthyroidism; one developed grade 4 liver toxicity (resolved with supportive management). We compared this strategy with cryoablation and/or ipilimumab. Dual ICB plus cryoablation induced higher expression of T cell activation markers and serum Th1 cytokines and reduced immunosuppressive serum CD4+PD-1hi T cells, improving effector-to-suppressor T cell ratio. After dual ICB and before cryoablation, T cell receptor sequencing of 4 patients showed increased T cell clonality. In this small subset of patients, we provide preliminary evidence that preoperative cryoablation plus ipilimumab and nivolumab is feasible, inducing systemic adaptive immune activation potentially more robust than cryoablation with/without ipilimumab.

5.
Res Sq ; 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38746324

RESUMEN

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8-16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

6.
EMBO Mol Med ; 16(8): 1957-1980, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38956205

RESUMEN

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.


Asunto(s)
Neoplasias de la Mama , Resistencia a Antineoplásicos , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/genética , Humanos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Femenino , Animales , Línea Celular Tumoral , Ratones , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Transducción de Señal/efectos de los fármacos
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