Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel.

: Pancreatic ductal adenocarcinoma acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding some biological mechanisms of chemoresistance, much about those mechanisms remains to be uncovered. Mechanobiology, which studies the physical properties of cells, holds promise as a potential target for addressing the challenges of chemoresistance in PDAC.

The effect of cancer-associated mutations on ligand binding and receptor function - A case for the 5-HT receptor.

The serotonin 5-HT receptor is a G protein-coupled receptor (GPCR) mainly expressed in the central nervous system. Besides regulating mood, appetite, and reproductive behavior, it has been identified as a potential target for cancer treatment. In this study, we aimed to investigate the effects of cancer patient-derived 5-HT receptor mutations on ligand binding and receptor functionality.

TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues.

CD3-engaging bispecific antibodies trigger a paracrine regulated wave of T-cell recruitment for effective tumor killing.

The mechanism of action of bispecific antibodies (bsAbs) directing T-cell immunity to solid tumors is incompletely understood. Here, we screened a series of CD3xHER2 bsAbs using extracellular matrix (ECM) embedded breast cancer tumoroid arrays exposed to healthy donor-derived T-cells. An initial phase of random T-cell movement throughout the ECM (day 1-2), was followed by a bsAb-dependent phase of active T-cell recruitment to tumoroids (day 2-4), and tumoroid killing (day 4-6).

GRHL2 suppression of NT5E/CD73 in breast cancer cells modulates CD73-mediated adenosine production and T cell recruitment.

Tumor tissues often contain high extracellular adenosine, promoting an immunosuppressed environment linked to mesenchymal transition and immune evasion. Here, we show that loss of the epithelial transcription factor, GRHL2, triggers NT5E/CD73 ecto-enzyme expression, augmenting the conversion of AMP to adenosine. GRHL2 binds an intronic sequence and is negatively correlated with NT5E/CD73 in breast cancer cell lines and patients.

ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.

Methods: Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established.

Differential Sensitivity to Ionizing Radiation in Gemcitabine-Resistant and Paclitaxel-Resistant Pancreatic Cancer Cells.

Purpose: Chemoresistance remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). Although chemoradiation has proven effective in other tumor types, such as head and neck squamous cell carcinoma, its role in PDAC and effect on acquired chemoresistance have yet to be fully explored. In this study, we investigated the sensitivity of gemcitabine-resistant (GR) and paclitaxel-resistant (PR) PDAC cells to ionizing radiation (IR) and their underlying mechanisms.

Cancer-Associated Fibroblasts Are Key Determinants of Cancer Cell Invasion in the Earliest Stage of Colorectal Cancer.

Background & Aims: Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression.

Differential response of luminal and basal breast cancer cells to acute and chronic hypoxia.

Hypoxia is linked to disease progression and poor prognosis in several cancers, including breast cancer. Cancer cells can encounter acute, chronic, and/or intermittent periods of oxygen deprivation and it is poorly understood how the different breast cancer subtypes respond to such hypoxia regimes. Here, we assessed the response of representative cell lines for the luminal and basal A subtype to acute (24 h) and chronic hypoxia (5 days).

GRHL2 Regulation of Growth/Motility Balance in Luminal versus Basal Breast Cancer.

The transcription factor Grainyhead-like 2 (GRHL2) is a critical transcription factor for epithelial tissues that has been reported to promote cancer growth in some and suppress aspects of cancer progression in other studies. We investigated its role in different breast cancer subtypes. In breast cancer patients, GRHL2 expression was increased in all subtypes and inversely correlated with overall survival in basal-like breast cancer patients.

Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC).

Introduction: PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine.

GRHL2-controlled gene expression networks in luminal breast cancer.

Grainyhead like 2 (GRHL2) is an essential transcription factor for development and function of epithelial tissues. It has dual roles in cancer by supporting tumor growth while suppressing epithelial to mesenchymal transitions (EMT). GRHL2 cooperates with androgen and estrogen receptors (ER) to regulate gene expression.

Crosstalk between Hypoxia and Extracellular Matrix in the Tumor Microenvironment in Breast Cancer.

Even though breast cancer is the most diagnosed cancer among women, treatments are not always successful in preventing its progression. Recent studies suggest that hypoxia and the extracellular matrix (ECM) are important in altering cell metabolism and tumor metastasis. Therefore, the aim of this review is to study the crosstalk between hypoxia and the ECM and to assess their impact on breast cancer progression.

Hypoxia Triggers TAZ Phosphorylation in Basal A Triple Negative Breast Cancer Cells.

Hypoxia and HIF signaling drive cancer progression and therapy resistance and have been demonstrated in breast cancer. To what extent breast cancer subtypes differ in their response to hypoxia has not been resolved. Here, we show that hypoxia similarly triggers HIF1 stabilization in luminal and basal A triple negative breast cancer cells and we use high throughput targeted RNA sequencing to analyze its effects on gene expression in these subtypes.

Cancer-Associated Mutations of the Adenosine A Receptor Have Diverse Influences on Ligand Binding and Receptor Functions.

The adenosine A receptor (AAR) is a class A G-protein-coupled receptor (GPCR). It is an immune checkpoint in the tumor micro-environment and has become an emerging target for cancer treatment. In this study, we aimed to explore the effects of cancer-patient-derived AAR mutations on ligand binding and receptor functions.

High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors.

Cells can adjust their mitochondrial morphology by altering the balance between mitochondrial fission and fusion to adapt to stressful conditions. The connection between a chemical perturbation, changes in mitochondrial function, and altered mitochondrial morphology is not well understood. Here, we made use of high-throughput high-content confocal microscopy to assess the effects of distinct classes of oxidative phosphorylation (OXPHOS) complex inhibitors on mitochondrial parameters in a concentration and time resolved manner.

Spatial and Temporal Modulation of Cell Instructive Cues in a Filamentous Supramolecular Biomaterial.

Supramolecular materials provide unique opportunities to mimic both the structure and mechanics of the biopolymer networks that compose the extracellular matrix. However, strategies to modify their filamentous structures in space and time in 3D cell culture to study cell behavior as encountered in development and disease are lacking. We herein disclose a multicomponent squaramide-based supramolecular material whose mechanics and bioactivity can be controlled by light through co-assembly of a 1,2-dithiolane (DT) monomer that forms disulfide cross-links.

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities.

Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell-matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment.

Substrate rigidity modulates traction forces and stoichiometry of cell-matrix adhesions.

In cell-matrix adhesions, integrin receptors and associated proteins provide a dynamic coupling of the extracellular matrix (ECM) to the cytoskeleton. This allows bidirectional transmission of forces between the ECM and the cytoskeleton, which tunes intracellular signaling cascades that control survival, proliferation, differentiation, and motility. The quantitative relationships between recruitment of distinct cell-matrix adhesion proteins and local cellular traction forces are not known.

Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors.

Mitochondria are the main bioenergetic organelles of cells. Exposure to chemicals targeting mitochondria therefore generally results in the development of toxicity. The cellular response to perturbations in cellular energy production is a balance between adaptation, by reorganisation and organelle biogenesis, and sacrifice, in the form of cell death.

Therapy-Naive and Radioresistant 3-Dimensional Pancreatic Cancer Cell Cultures Are Effectively Radiosensitized by β1 Integrin Targeting.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with unmet needs. The role of highly conformal radiation therapy is still under debate for PDAC. Owing to its desmoplastic nature, integrin-mediated interactions between PDAC cells and extracellular matrix (ECM) profoundly contribute to PDAC therapy resistance.

Correction: Görte et al. Comparative Proton and Photon Irradiation Combined with Pharmacological Inhibitors in 3D Pancreatic Cancer Cultures. 2020, , 3216.

The authors wish to make the following corrections to this paper [...