Biology subjects

Pollak, M.

Publications and source records attributed to Pollak, M..

7 recordsLinked to original sources

bioRxiv2026

A therapeutic vulnerability linking MNK1/2 inhibition and G1/S cyclin-dependent kinase blockade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a clinically challenging disease with limited therapeutic options. MAP kinase-interacting kinases 1 and 2 (MNK1/2)-mediated phosphorylation of eukaryotic initiation factor 4E (eIF4E) promotes oncogenic translation and represents a potential therapeutic target. We previously showed that loss of eIF4E phosphorylation suppresses metastasis but not primary tumor growth. Here, an shRNA screen surveying druggable genes unveiled cyclin-dependent kinase 4 (CDK4) as a genetic vulnerability to MNK1/2 inhibition in MDA-MB-231 TNBC cells. Although CDK4/6 inhibitors are approved for hormone receptor (HR)-positive, HER2-negative breast cancer, they are not approved for TNBC. We demonstrate that MNK1/2 inhibition synergizes with CDK4/6 blockade suppresses TNBC cell growth, a synergy also observed in another independent TNBC cell line (SUM159) using a broader G1/S CDK (CDK2/4/6) inhibitor. Integrated RNA sequencing and ribosome profiling revealed combination-specific changes in translation associated with mitotic checkpoint control and DNA repair. Our findings document MNK1/2 inhibition as a strategy to sensitize TNBC to G1/S CDK inhibition and provide a new avenue for therapeutic combination.

cancer biology↗

bioRxiv2026

Developmentally programmed nuclear pore complex replacement enables oocyte specification

Oocytes endow embryos with molecular machinery essential for development, but not all maternal components are inherited indiscriminately. In Drosophila, surveillance pathways eliminate defective mitochondria and aberrant RNAs from the maternal pool. Whether stable nuclear structures, like nuclear pore complexes (NPCs), are similarly curated remains unknown. Here, we uncover a developmentally programmed NPC turnover pathway that renews NPCs during oocyte specification. NPC levels decline through a combination of passive dilution, driven by deferred nucleoporin expression, and active degradation mediated by the ESCRT-III/Vps4 pathway. This clearance is counterbalanced by subsequent de novo NPC synthesis. Failure to turn over NPCs results in aberrantly persistent germ cell gene expression and defective oocyte specification. These findings establish NPC renewal as a critical step in oocyte identity establishment and maternal provisioning.

developmental biology↗

bioRxiv2024

Reduction in ETFDH expression optimizes cancer cell bioenergetics

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM-6 cells, and its expression is reduced across human cancers. ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics and accelerates neoplastic growth by activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerate neoplastic growth.

cancer biology↗

bioRxiv2023

Tirzepatide inhibits tumor growth in mice with diet-induced obesity

Tirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can lead to weight loss up to [~] 20% in overweight patients. Obesity has been shown to increase risk and/or to worsen prognosis of certain common cancers, including colon cancer, but the effect of tirzepatide on neoplasia has not been examined in detail. We studied the effects of this drug on the murine MC38 colon cancer model, which has previously shown to exhibit accelerated growth in hosts with diet-induced obesity. Tirzepatide did not cause tumor regression, but reduced tumor growth rates by [~] 50%. This was associated with substantial reductions in food intake, and in circulating levels of insulin and leptin. Tirzepatide had no effect on MC38 cancer cell proliferation in vitro, and the effect of tirzepatide on tumor growth in vivo could be phenocopied in placebo treated mice simply by restricting food intake to the amount consumed mice receiving the drug. This provides evidence that the drug acts indirectly to inhibit tumor growth. Our findings raise the possibility that use of tirzepatide or similar agents may benefit patients with obesity-related cancers.

cancer biology↗

bioRxiv2022

Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

cancer biology↗

bioRxiv2019

Proteolytic program-dependent functions are impaired in INF2-mediated focal segmental glomerulosclerosis.

Regulation of the actin cytoskeleton is critical for normal glomerular podocyte structure and function. Altered regulation of the podocyte cytoskeleton can lead to proteinuria, reduced kidney filtration function and focal segmental glomerulosclerosis (FSGS). Mutations in inverted formin 2 (INF2), a member of the formin family of actin regulatory proteins, are the most common cause of autosomal dominant FSGS. INF2 is a multi-domain protein regulated by interaction between its N-terminal Diaphanous Inhibitory Domain (DID) and its C-terminal Diaphanous Auto-regulatory Domain (DAD). Although many aspects of the INF2 DID-DAD interaction are understood, it remains unclear why disease-causing mutations are restricted to the DID and how these mutations cause human disease. Here we report a proteolytic cleavage in INF2 that liberates the INF2 N-terminal DID to function independently of the INF2 C-terminal fragment containing the DAD domain. N-terminal DID region epitopes are differentially localized to podocyte foot process structures in normal glomeruli. This N-terminal fragment localization is lost in INF2-mediated FSGS, whereas INF2 C-terminal fragment epitopes localize to the podocyte cell body in both normal and disease conditions. INF2 cleavage is mediated by cathepsin proteases. In cultured podocytes, the wild-type INF2 N-terminal fragment localizes to membrane regions and promotes cell spreading, while these functions are impaired in a disease-associated INF2 mutant R218Q in the DID. These features are dependent on INF2-cleavage, with accompanying interaction of INF2 N-fragment with mDIA1. Our data suggest a unique cellular function of the DID dependent on INF2 cleavage and help explain the altered localization of FSGS-associated INF2 mutant polypeptides.

pathology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗