Glucocorticoid Receptor Signaling Mediates Resistance to Therapy in Matrix Rigidity-Induced Dormant Brain Metastatic Breast Cancer Spheroids.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in females. Approximately 20-30% of patients with advanced breast cancer develop brain metastasis. Often, brain metastatic breast cancer (BMBC) exhibits a nonproliferative (dormant) phenotype and therapy resistance due to the unfavorable organ microenvironment.

Hypoxic stress incites HIF1α-driven ribosome biogenesis that can be exploited by targeting RNA Polymerase I.

Intratumoral low oxygen tension promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) is the principal transcription factor orchestrating cellular responses to hypoxic stress, mediating the regulation of genes implicated in adapting to perturbations in oxygen homeostasis. Here, we describe our findings that functionally demonstrate a nucleolar localization domain in HIF1ɑ that enables HIF1ɑ to translocate to the nucleolus.

Nucleolar proteomics identifies S100A16 as a key nucleolar protein driving breast cancer metastasis.

Metastasis is the leading cause of poor clinical outcomes in solid tumors; yet despite recent advances many of the driving factors of metastasis remain poorly understood. Tumor cells that successfully metastasize are subject to numerous stress points from intrinsic and extrinsic factors that the cell must overcome to survive and colonize a secondary site. The nucleolus, the site of ribosome biogenesis, serves as a central hub for sensing and responding to cellular stress and plays a crucial role in this process; furthermore, emerging evidence highlights the potential role of ribosome biogenesis in driving metastasis.

Ribosome Biogenesis Underpins Tumor Progression: A Comprehensive Signature for Survival and Immunotherapy Response Prediction.

: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite "PanRibo-515 score" reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore its relationship with immune checkpoint therapy outcomes. : We curated 515 RiBi-associated genes (PanRibo-515) and used a LASSO regression-based strategy on a training dataset (GSE202203) to select the prognostically most relevant subset of 68 genes (OncoRibo-68).

PET Imaging of Diabetes-Induced Alterations in Metabolism and Immune Activation.

Introduction: Obesity and type 2 diabetes (T2D) influence the tumor microenvironment by altering glucose metabolism, which has been shown to decrease immune cell infiltration and activation. Positron emission tomography (PET) imaging provides a non-invasive method to detect molecular markers of immune populations in the tumor microenvironment and systemic organs. The goal of this study is to utilize advanced molecular imaging to quantify differences in innate and adaptive immune responses in diabetic obese mice systemically and within the tumor microenvironment.

Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression.

Macrophages are important cellular components of the innate immune system, serving as the first line of immune defense. They are also among the first immune cells to be reprogrammed by the evolving tumor milieu into tumor-supportive macrophages that facilitate tumor progression and promote therapeutic evasion. In this study, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes, indicating that this is an early event that is maintained in the tumor tissue.

The metastatic cascade through the lens of therapeutic inhibition.

Metastasis is a main cause of cancer-related death, and a deeper understanding of the metastatic process will inform more targeted and mechanistic approaches that can abrogate challenges in treatment efficacy and toxicity. Several steps throughout the metastatic cascade, from angiogenesis to secondary tumor formation, offer specific vulnerabilities to therapies that can lead to the decline or cessation of metastatic progression. A deeper understanding of the metastatic cascade also allows combination systemic therapies to be used synergistically.

Matrix stiffness influences response to chemo and targeted therapy in brain metastatic breast cancer cells.

Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to distant organs (, brain), wherein they can exhibit a dormant phenotype for extended time periods.

Laminin I mediates resistance to lapatinib in HER2-positive brain metastatic breast cancer cells in vitro.

The role of extracellular matrix (ECM) prevalent in the brain metastatic breast cancer (BMBC) niche in mediating cancer cell growth, survival, and response to therapeutic agents is not well understood. Emerging evidence suggests a vital role of ECM of the primary breast tumor microenvironment (TME) in tumor progression and survival. Possibly, the BMBC cells are also similarly influenced by the ECM of the metastatic niche; therefore, understanding the effect of the metastatic ECM on BMBC cells is imperative.

Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer.

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial-mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT.

Protocol for generating dormant human brain metastatic breast cancer spheroids in vitro.

Here, we present a protocol to generate dormant brain metastatic breast cancer (BMBC) spheroids utilizing hyaluronic acid (HA) hydrogels. We describe the steps for construction of spheroids from human BMBC cell lines MDA-MB-231Br and BT474Br3, HA hydrogel preparation, and spheroid plating on HA hydrogels and in suspension culture. We then detail the impact of HA hydrogel on the dormant phenotype of spheroids by measuring spheroid cross-sectional area, cell numbers, and EdU staining.

Ribosome biosynthesis and Hedgehog activity are cooperative actionable signaling mechanisms in breast cancer following radiotherapy.

Hyperactivated ribosome biosynthesis is attributed to a need for elevated protein synthesis that accommodates cell growth and division, and is characterized by nucleomorphometric alterations and increased nucleolar counts. Ribosome biogenesis is challenged when DNA-damaging treatments such as radiotherapy are utilized. Tumor cells that survive radiotherapy form the basis of recurrence, tumor progression, and metastasis.

Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression.

A Biomimetic Hyaluronic Acid Hydrogel Models Mass Dormancy in Brain Metastatic Breast Cancer Spheroids.

Approximately 90% of breast cancer related mortalities are due to metastasis to distant organs. At the metastatic sites, cancer cells are capable of evading death by exhibiting cellular or mass dormancy. However, the mechanisms involved in attaining dormancy at the metastatic site are not well understood.

Hedgehog blockade remodels the gut microbiota and the intestinal effector CD8 T cells in a mouse model of mammary carcinoma.

Given the gut microbiome's rise as a potential frontier in cancer pathogenesis and therapy, leveraging microbial analyses in the study of breast tumor progression and treatment could unveil novel interactions between commensal bacteria and disease outcomes. In breast cancer, the Hedgehog (Hh) signaling pathway is a potential target for treatment due to its aberrant activation leading to poorer prognoses and drug resistance. There are limited studies that have investigated the influences of orally administered cancer therapeutics, such as Vismodegib (a pharmacological, clinically used Hh inhibitor) on the gut microbiota.

Ribosome Biogenesis: A Central Player in Cancer Metastasis and Therapeutic Resistance.

Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways.

Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape.

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis.

Hedgehog Signaling Regulates Metabolism and Polarization of Mammary Tumor-Associated Macrophages.

Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages.

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis.

The nucleolus of a cell is a critical cellular compartment that is responsible for ribosome biogenesis and plays a central role in tumor progression. Fisetin, a nutraceutical, is a naturally occurring flavonol from the flavonoid group of polyphenols that has anti-cancer effects. Fisetin negatively impacts several signaling pathways that support tumor progression.

Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors.

Molecular dynamics of developmental processes are repurposed by cancer cells to support cancer initiation and progression. Disruption of the delicate balance between cellular differentiation and plasticity during mammary development leads to breast cancer initiation and metastatic progression. STAT5A is essential for differentiation of secretory mammary alveolar epithelium.

Informing the new developments and future of cancer immunotherapy : Future of cancer immunotherapy.

The application of cancer immunotherapy (CIT) in reinforcing anti-tumor immunity in response to carcinogenesis and metastasis has shown promising advances, along with new therapeutic challenges, in the landscape of cancer care. To promote tumor growth and metastasis, cancer cells aim to manipulate their microenvironment by mediating a crosstalk with various immune cells through the secretion of chemokines, cytokines, and other associated factors. Understanding this crosstalk is the key to discovering the best targets for improved immunotherapies and clinical strategies in cancer treatment.