Biology subjects

Seen, M.

Publications and source records attributed to Seen, M..

5 recordsLinked to original sources

bioRxiv2026

Unraveling AMPK and BET regulation of immune checkpoint biology: implications for personalized medicine

Triple negative breast cancer (TNBC) patients with comorbid Type 2 diabetes (T2D) show worse survival compared to nondiabetic TNBC patients. Immune checkpoint blockade (ICB) has unclear benefit in TNBC. Immune suppression in T2D, and use of metformin, an activator of 5 Adenosine Monophosphate-activated Protein Kinase (AMPK), in such patients, prompted us to examine AMPK regulation of immune checkpoint expression. Improved ICB efficacy may optimize outcomes for certain TNBC patients. We have also been exploring the role of Bromodomain and ExtraTerminal domain (BET) proteins (BRD2, BRD3, BRD4) in regulation of checkpoint molecules in immune cell subsets, including CD4+, CD8+ T cells, and NK cells. BET proteins are important transcriptional co-regulators, critical for proliferation and metastasis in many cancer types, including TNBC. We observed differential BET regulation of immune checkpoint proteins, specifically TIM-3, TIGIT, PD-1 and CTLA-4, on CD3/CD28-stimulated peripheral blood mononuclear cells by flow cytometry. Chemical inhibition of AMPK with Compound C, and with the pan-BET inhibitor JQ1 or the BRD4-selective PROTAC inhibitor MZ-1, revealed that BET proteins regulate PD-1 and CTLA-4 through an AMPK-dependent pathway and TIM-3 and TIGIT through an AMPK-independent pathway. Personalized approaches to ICB treatment of TNBC patients with comorbid T2D should improve outcomes.

cancer biology↗

bioRxiv2025

Metabolic medications modify prostate cancer progression through exosome reprogramming

Among prostate cancer patients, co-morbid Type 2 Diabetes (T2D) is associated with faster progression to biochemical recurrence and increased risk of mortality. Previous work from our lab provides evidence that exosomes purified from media of insulin resistant adipocytes or T2D patient plasma likely drives these outcomes by delivering miRNAs that exacerbate tumor aggressiveness in several breast and prostate cancer models. Here, we build on our previous findings to investigate whether treatment with metabolic medications attenuates the tumor promoting effects of exosomes. We found that human DU145 cells, a model for prostate cancer, treated with plasma exosomes from T2D patients, shows patterns in global gene transcription that resolve by patient treatment with metformin. To test the effects of metformin experimentally, we used a murine model of insulin resistance (IR). Treating DU145 cells with miRNAs purified from the plasma exosomes of IR mice, we found that cells transfected with miRNAs from the metformin-treated IR group displayed significantly less migration than cells transfected with miRNAs from the unmedicated IR group. We suggest that metformin may partially reverse effects of T2D to exacerbate tumor aggressiveness by modifying the miRNA payload of plasma exosomes.

cancer biology↗

bioRxiv2024

Plasma Exosomes in Insulin Resistant Obesity Exacerbate Progression of Triple Negative Breast Cancer

Breast cancer, the most common cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes from diet-induced obesity mice induce epithelial-mesenchymal transition features in TNBC cells, leading to increased migration in vitro and enhanced metastasis in vivo. We build on our previous reports demonstrating that plasma exosomes from obese, diabetic patients, and exosomes from insulin-resistant 3T3-L1 adipocytes, upregulate key transcriptional signatures of epithelial-mesenchymal transition in breast cancer. Bioinformatic analysis reveals that TNBC cells exhibit higher expression and activation of proteins related to the Rho-GTPase cascade, particularly the small Ras-related protein Rac1. Our approach suggests novel therapeutic targets and exosomal biomarkers, ultimately to improve prognosis for TNBC patients with co-morbid metabolic disorders.

cancer biology↗

bioRxiv2024

Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids

Women with obesity-driven diabetes (T2D) are predisposed to more aggressive breast cancers, yet patient metabolic status does not fully inform current standards of care. We previously identified plasma exosomes as key mediators of intercellular communication and drivers of tumor progression; however, their effect on immune cells within the tumor microenvironment (TME) remains unclear. To model this exosomal signaling, we developed a novel method to generate patient-derived organoids (PDOs) from breast tumor resections, uniquely preserving native tumor-infiltrating lymphocytes (TILs) for the first time. This modifiable and reproducible system provides a robust platform for studying human tumor-immune interactions within the TME in vitro. After 3-day exosome treatment, we assessed the impact of T2D-derived exosomes on PDOs via single-cell RNA sequencing. Exosomes from T2D patient plasma triggered a 13.6-fold expansion of immunosuppressive TILs compared to non-diabetic exosome controls. This immune dysfunction may permit the survival of micrometastases and undermine immune checkpoint therapies, a known challenge for cancer patients with comorbid T2D. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and approximately 2.3-fold upregulation of epithelial-to-mesenchymal transition, invasiveness, and cancer stemness, consistent with enhanced tumor aggressiveness and metastatic potential of these PDOs. These findings demonstrate how metabolic dysregulation in T2D disrupts tumor-immune crosstalk, profoundly impairing anti-tumor immunity and driving cancer progression through a previously underappreciated exosomal signaling pathway. These insights into the TME could inform personalized treatments for patients with this comorbidity.

cancer biology↗

bioRxiv2024

Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes

Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis. SignificanceIR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.

cancer biology↗