Biology subjects

Seen, M.

Publications and source records attributed to Seen, M..

3 recordsLinked to original sources

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↗