Biology subjects

Ferbeyre, G.

Publications and source records attributed to Ferbeyre, G..

11 recordsLinked to original sources

bioRxiv2026

Targeting ribosome biogenesis sensitizes PARPi-resistant triple-negative breast cancer

Poly (ADP-ribose) polymerase inhibitors (PARPi) are the only targeted treatment available for early triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options. While PARPi are effective in patients with BRCA mutations, resistance to these inhibitors can arise. We previously developed BRCA-mutant cell lines, HCC1395, with acquired resistance to talazoparib and olaparib, and have now developed PARPi-resistant MX1 cell lines in an analogous manner. Ribosomal pathways were upregulated in 3/4 cell lines with acquired PARPi resistance. The resistant cell lines showed high and low basal nucleolar stress based on nucleolar morphology and nucleophosmin delocalization from nucleolus to nucleoplasm. Treatment of these cell lines with the combination of olaparib and a ribosome biogenesis inhibitor, BMH-21, demonstrated synergy in the PARPi-resistant cell lines, but not in the parental cells. Interestingly, HCC1395 cells, which had lower baseline nucleolar stress, showed greater nucleophosmin delocalization with combination treatment than MX1 cells, which had higher baseline nucleolar stress. All four cell lines demonstrated sustained DNA damage with the combination. We extended our investigation to 3 BRCA wild-type TNBC cell lines, BT549, Hs578T, and MDAMB231 and identified synergy in the context of intrinsic PARPi resistance. In MDAMB231 cells, combining olaparib with BMH-21 induced a senescence-like phenotype, increasing gH2AX-positive cells by up to 7.3-fold, senescence-associated B-galactosidase (SA-B-gal) staining by 5.6-fold, and p21 by 3.6-fold. These results were mirrored with a second ribosome biogenesis inhibitor, CX-5461. Finally, we identified distinct patterns of ribosomal pathway activity in a cohort of patients with treatment-resistant TNBC, and found correlations between ribosomal pathways with MYC, proliferation, DNA damage, and senescence. Together, these data identify ribosome biogenesis as a potential therapeutic vulnerability in PARPi-resistant TNBC and support its targeting in combination with PARPi, while demonstrating a broader for ribosome biogenesis in treatment-resistant TNBC.

cancer biology↗

bioRxiv2026

Lactate-fueled hydride transfer metabolon drives breast cancer metastasis

Metabolic plasticity of cancer cells plays a major role in metastasis. Use of alternative carbon fuels (e.g., lactate) boosts metabolic plasticity, but the underlying mechanisms remain obscure. We show that lactate dehydrogenase B (LDHB) cooperates with the hydride ion transfer complex (HTC) comprised of pyruvate carboxylase (PC), malic enzyme (ME1) and malate dehydrogenase (MDH1) to form a metabolon that confers metabolic flexibility through lactate assimilation under physiological conditions. HTC/LDHB metabolon assembles in the aggressive breast cancer subtypes and reprograms nicotinamide adenine dinucleotide (NAD) metabolism to promote migration, invasion and escape from anoikis - thereby driving metastasis. Altogether, this work identifies a lactate-fueled metabolon that propels metastatic dissemination of breast cancer.

Cancer Biology↗

bioRxiv2026

SOCS1 expression in prostate epithelial cells is essential for tissue homeostasis and tumor suppression

Suppressor of cytokine signaling 1 (SOCS1) negative regulates inflammatory cytokine production and attenuates oncogenic growth factor signaling pathways. Reduced SOCS1 protein expression in human prostate cancer correlates with greater disease severity. To define the physiological functions of SOCS1 functions in the prostate, we conditionally ablated Socs1 in prostate epithelial cells of C57BL/6 mice. These Socs1{Delta}PE mice exhibited normal prostate development, maturation and lobular architecture. However, adult Socs1{Delta}PEmice developed progressive epithelial hyperplasia and inflammatory cell infiltration that were temporally and spatially distinct. SOCS1-deficient prostate showed increased epithelial cell proliferation and elevated oxidative stress markers, and prostate organoids recapitulated this hyperplasia phenotype. Diet-induced obesity exacerbated both hyperplasia and inflammation in SOCS1-deficient prostate. Upon transurethral infection with uropathogenic Escherichia coli UPEC1677 expressing the genotoxin colibactin, Socs1{Delta}PE mice developed invasive prostate cancer with complete loss of lobular architecture, whereas control mice developed hyperplasia and pre-neoplastic lesions. In vitro, SOCS1-deficient prostate organoid-derived epithelial cells exhibited increased DNA damage following exposure to UPEC1677. Deletion of the colibactin biosynthetic gene clbP in UPEC1677 abolished its ability to induce DNA damage in SOCS1-deficient cells and to drive prostate cancer in vivo. Proteomic analysis of prostate organoids revealed dysregulation of basal and luminal epithelial lineage markers and signaling pathway proteins that could promote neoplasia in SOCS1-deficient cells. Collectively, these findings establish an essential, epithelial cell-intrinsic role for SOCS1 in maintaining prostate tissue homeostasis by restraining proliferation, regulating lineage plasticity, limiting inflammation and oxidative stress, and conferring protection against genotoxic injury and neoplastic transformation.

cancer biology↗

bioRxiv2026

Senescent fibroblasts interfere with the tumor immune response in humanized models by inducing neutrophil extracellular traps

Neutrophils are known to promote tumor progression and metastasis, in part through the release of extracellular traps (NETs), a phenomenon associated with poor prognosis in patients. Here, we demonstrate that senescent fibroblasts, via their senescence-associated secretory phenotype (SASP), promote the recruitment of CD33+ myeloid cells and impair the tumor immune response in an orthotopic humanized mouse lung cancer model. Mechanistically, we found that therapy-induced senescence triggers the formation of NETs, which interfere with immune cell infiltration in tumor spheroids. This phenotype was reversible upon treatment with DNAse I or Reparixin, an inhibitor of the action of CXCL8/IL-8 and CXCL1/GRO1, two key SASP factors. Furthermore, we show that senescence-induced NETs favor lung metastasis in a humanized mouse model, a phenotype that was inhibited by DNase I treatment. Our findings provide critical insights into the complex interplay between cellular senescence, NETosis, and the tumor immune response, highlighting another mechanism by which senotherapies can improve cancer treatments.

cell biology↗

bioRxiv2024

The Role of ATP Synthase Subunit e (ATP5I) in Mediating the Metabolic and Antiproliferative Effects of Biguanides

Here we identify the subunit e of F F -ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F F -ATP synthase dimers which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro and disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide treated cells including mitochondrial morphology alterations, reduction of the NAD+/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers and a compensatory increase in glycolysis. Notably, metformin affects the oligomerization of the F F -ATP synthase leading to accumulation of vestigial assembly intermediates also observed upon ATP5I inactivation. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and anti-proliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F F -ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.

cancer biology↗

bioRxiv2024

Biguanide-PROTACs: Modulating Mitochondrial Proteins in Pancreatic Cancer Cells

This study focuses on the synthesis of Biguanide-PROTACs, formed by conjugating the biguanide motif with diverse E3 enzyme ligands and spacers. Evaluation of their activity on pancreatic cancer cell (KP4) proliferation established a correlation between membrane permeability and median effective concentration. Mechanistic insights revealed that only two compounds exhibited biguanide-like AMPK activation, while only one hydrophobic compound uniquely altered mitochondrial protein levels. The prospect of developing and expanding the Biguanide-PROTAC library holds promises, offering potential insights into biguanide mechanisms and the creation of more potent anticancer agents. This study contributes to understanding the intricate interplay between compound structure, permeability, and anticancer activity, paving the way for targeted drug development in pancreatic cancer treatment.

cancer biology↗

bioRxiv2021

SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma

SOCS1 and SOCS3 genes, frequently repressed in hepatocellular carcinoma (HCC), function as tumor suppressors in hepatocytes. However, TCGA transcriptomic data revealed that SOCS1-low/SOCS3-high specimens displayed more aggressive HCC than SOCS1-low/SOCS3-low cases. We show that hepatocyte-specific Socs1-deficient livers upregulate Socs3 expression following genotoxic stress. Whereas deletion of Socs1 or Socs3 increased HCC susceptibility, ablation of both genes attenuated HCC growth. SOCS3 promotes p53 activation in SOCS1-deficient livers, leading to increased expression of CDKN1A (p21WAF1/CIP1), which coincides with elevated expression and transcriptional activity of NRF2. Deleting Cdkn1a in SOCS1-deficient livers diminished NRF2 activation, oxidative stress and HCC progression. Elevated CDKN1A expression and enrichment of antioxidant response genes also characterized SOCS1-low/SOCS3-high HCC. SOCS1 expression in HCC cell lines reduced oxidative stress, p21 expression and NRF2 activation. Our findings demonstrate that SOCS1 controls the oncogenic potential of SOCS3-driven p53-p21-NRF2 axis and suggest that NRF2-mediated antioxidant response represents a drug target in SOCS1-deficient HCC.

cancer biology↗

bioRxiv2019

Phenylethynylbenzyl-Modified Biguanides Inhibit Pancreatic Cancer Tumor Growth

We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth/viability of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improved mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound 1b, like metformin, decreases the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies with, the most active, compound 1b show a significant growth inhibition of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had no activity.

cancer biology↗

bioRxiv2019

The retinoblastoma tumor suppressor limits ribosomal readthrough during oncogene induced senescence

The origin and evolution of cancer cells is considered to be mainly fueled by mutations affecting the DNA sequence. Although errors in translation could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called \"caretakers\" block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretakers genes will prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the retinoblastoma protein (RB) acts as caretaker tumor suppressor by preventing the readthrough of termination codons, a process that allows proteins to be synthetized with additional domains. In particular, we show that expression of oncogenic ras in normal human cells triggers a cellular senescence response characterized by a significant reduction of basal ribosomal readthrough. However, inactivation of the RB tumor suppressor pathway in these cells, using the viral oncoprotein E7 or the oncogenic kinase CDK4 increased readthrough. Conversely, activation of the RB pathway by the tumor suppressor PML, the ribosomal proteins RPS14/uS11 and RPL22/eL22 or the CDK4/6 inhibitor palbociclib reduced readthrough. We thus reveal a novel function for the RB pathway as a caretaker of translational errors with implications for tumor suppression and cancer treatment.

molecular biology↗

bioRxiv2017

Senescence associated protein degradation

Senescent cells accumulate with age and contribute to pathologies associated to old age. The senescent program can be induced by pro-cancer stimuli or is developmentally controlled. In cells forced to senesce by expression of oncogenes or short telomeres, aberrant activation of the ERK/MAP kinase signaling pathway leads to selective protein degradation by the ubiquitin proteasome system. The proteins affected by this process control key cellular processes known to be defective in senescent cells. We discuss the evidence supporting a general role for senescence associated protein degradation for organismal aging.

cell biology↗

bioRxiv2016

Senescence gives insights into the morphogenetic evolution of anamniotes.

Summary statementWe report the presence of senescent cells in several transient structures in developing amphibian and teleost fish, suggesting novel mechanisms of morphogenesis that appeared early in vertebrate evolution.\n\nAbstractSenescence represents a mechanism to avoid undesired cell proliferation that plays a role in tumor suppression, wound healing and embryonic development. In order to gain insight on the evolution of senescence, we looked at its presence in developing axolotls (urodele amphibians) and in zebrafish (teleost fish), which are both anamniotes. Our data indicate that cellular senescence is present in various developing structures in axolotls (pronephros, olfactory nerve fascicles, lateral organs, gums) and in zebrafish (epithelium of the yolk sac and in the lower part of the gut). Senescence was particularly associated with transient structures (pronephros in axolotls & yolk sac in zebrafish) suggesting that it plays a role in the elimination of these tissues. Our data supports the notion that cellular senescence evolved early in vertebrate evolution to influence embryonic development.

developmental biology↗