MACC1 Expression in Colorectal Cancer Is Upregulated by Loss of Epigenetic Repression Under Oxidative Stress Condition.

Reactive oxygen species (ROS) cause oxidative stress and contribute to cancer genesis and progression. Metastasis-associated in colon cancer 1 (MACC1) is a key metastasis-mediating transcription factor in colorectal cancer (CRC). Whether ROS epigenetically regulated MACC1 expression and increased tumor progression in CRC have not been elucidated so far.

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing.

Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated.

EPI-X4, a CXCR4 antagonist inhibits tumor growth in pancreatic cancer and lymphoma models.

Endogenous peptide inhibitor for CXCR4 (EPI-X4) is a CXCR4 antagonist with potential for cancer therapy. It is a processed fragment of serum albumin from the hemofiltrate of dialysis patients. This study reports the efficacy of fifteen EPI-X4 derivatives in pancreatic cancer and lymphoma models.

Clinically relevant glioblastoma patient-derived xenograft models to guide drug development and identify molecular signatures.

Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard of care drugs and efficacy of various new therapeutic approaches. There is a need for new therapies and models reflecting the complex biology of these tumors to analyze the molecular mechanisms of tumor formation and resistance, as well as to identify new therapeutic targets. We established and screened a panel of 26 patient-derived subcutaneous (s.

Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis.

Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration.

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells.

The circadian clock coordinates the timing of several cellular processes including transcription, the cell cycle, and metabolism. Disruptions in the clock machinery trigger the abnormal regulation of cancer hallmarks, impair cellular homeostasis, and stimulate tumourigenesis. Here we investigated the role of a disrupted clock by knocking out or knocking down the core-clock (CC) genes , or in cancer progression (e.

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies.

Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient's life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months.

MACC1-Induced Collective Migration Is Promoted by Proliferation Rather Than Single Cell Biomechanics.

Metastasis-associated in colon cancer 1 (MACC1) is a marker for metastasis, tumor cell migration, and increased proliferation in colorectal cancer (CRC). Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. Yet, many facets of the pro-migratory effects are not fully understood.

Calcium-binding protein S100P is a new target gene of MACC1, drives colorectal cancer metastasis and serves as a prognostic biomarker.

Background: The metastasis inducing gene MACC1 is a prognostic and predictive biomarker for metastasis in several cancers. Its mechanism of inducing metastasis includes the transcriptional control of other cancer-related target genes. Here, we investigate the interplay with the metastasis driver S100P in CRC progression.

Combination of Wnt/β-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer.

Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types.

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis.

Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate.

A Bioinformatic Pipeline to Identify Biomarkers for Metastasis Formation from RNA Sequencing Data.

Deep molecular characterization of tumors is a prerequisite for precision oncology and personalized anticancer treatment. Analyzing the tumor transcriptome by RNA sequencing (RNAseq) allows the quantification of individual isoforms and also the detection of sequence alteration in the expressed genes. This chapter describes an analysis pipeline that focuses both on accurate quantification of transcripts and on the occurrence of cancer-associated mutations.

MACC1 regulates clathrin-mediated endocytosis and receptor recycling of transferrin receptor and EGFR in colorectal cancer.

Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis.

MACC1 driven alterations in cellular biomechanics facilitate cell motility in glioblastoma.

Background: Metastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored.

Methods: We performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties of MACC1 overexpressing GBM cells.

Small Ones to Fight a Big Problem-Intervention of Cancer Metastasis by Small Molecules.

Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies.

Restoring Treatment Response in Colorectal Cancer Cells by Targeting MACC1-Dependent ABCB1 Expression in Combination Therapy.

Treatment failure of solid cancers, represented by the development of drug resistance in the primary tumor or later outgrowth of drug resistant metastases, is the major cause of death for cancer patients. It represents an urgent clinical need for predictive biomarkers which indicate the success or failure of standard treatment regimens. Besides treatment prediction, interfering with cellular processes associated with drug resistance might improve treatment response by applying combination therapies.

Circulating MACC1 Transcripts in Glioblastoma Patients Predict Prognosis and Treatment Response.

Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacks reliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associated in colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinical outcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher in patients compared to controls.

Pressurized intraperitoneal aerosol chemotherapy and its effect on gastric-cancer-derived peritoneal metastases: an overview.

This manuscript aspires to portray a review of the current literature focusing on manifest peritoneal metastasis (PM) derived from gastric cancer and its treatment options. Despite the development of chemotherapy and multimodal treatment options during the last decades, mortality remains high worldwide. After refreshing important epidemiological considerations, the molecular mechanisms currently accepted through which PM occurs are revised.

MACC1-the first decade of a key metastasis molecule from gene discovery to clinical translation.

Deciphering the paths to metastasis and identifying key molecules driving this process is one important issue for understanding and treatment of cancer. Such a key driver molecule is Metastasis Associated in Colon Cancer 1 (MACC1). A decade long research on this evolutionarily conserved molecule with features of a transcription factor as well as an adapter protein for versatile protein-protein interactions has shown that it has manifold properties driving tumors to their metastatic stage.

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients.

Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.

Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1.

MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds.

S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction.

The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin.

Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets.

The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy.

RNA Interference for Antimetastatic Therapy.

The suppression of genes involved in tumor progression, metastasis formation, or therapy resistance by RNA interference is a promising tool to treat cancer disease. Efficient delivery of interfering molecules and their sustained presence in tumor cells are required for therapeutic success. This chapter describes a method of systemic application of shRNA expression plasmid via tail vein injection in xenograft mice, causing the sustained reduction of target gene expression in the primary tumor.