Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling Signal Transduction

Ionizing radiation (IR) can promote migration and invasion of cancer cells, but the basis for this phenomenon has not been fully elucidated. IR increases expression of glucose-regulated protein 78kDa (GRP78) on the surface of cancer cells (CS-GRP78), and this up-regulation is associated with more aggressive behavior, radioresistance, and recurrence of cancer. Here, using various biochemical and immunological methods, including flow cytometry, cell proliferation and migration assays, Rho activation and quantitative RT-PCR assays, we investigated the mechanism by which CS-GRP78 contributes to radioresistance in pancreatic ductal adenocarcinoma (PDAC) cells. We found that activated α2-Macroglobulin (α2M*) a ligand of the CS-GRP78 receptor, induces formation of the AKT kinase (AKT)/DLC1 Rho-GTPase-activating protein (DLC1) complex and thereby increases Rho activation. Further, CS-GRP78 activated the transcriptional coactivators Yes-associated protein (YAP) and tafazzin (TAZ) in a Rho-dependent manner, promoting motility and invasiveness of PDAC cells. We observed that radiation-induced CS-GRP78 stimulates the nuclear accumulation of YAP/TAZ and increases YAP/TAZ target gene expressions. Remarkably, targeting CS-GRP78 with C38 monoclonal antibody (Mab) enhanced radiosensitivity and increased the efficacy of radiation therapy by curtailing PDAC cell motility and invasion. These findings reveal that CS-GRP78 acts upstream of YAP/TAZ signaling and promote migration and ra...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research

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and Purpose: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
Few studies have examined the role of stereotactic body radiation (SBRT) after multiagent chemotherapy (ChT) in pancreatic ductal adenocarcinoma (PDAC). This was a prospective study of SBRT after ChT for PDAC.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
Different prognostic markers have been identified in pancreatic cancer, including blood-based and imaging-based biomarkers. For example, lymphopenia can occur in patients receiving radiation therapy (RT) and is associated with decreased survival in several malignancies, including pancreatic ductal adenocarcinoma (PDAC) (Venkatesulu B, et al. Crit Rev Oncol Hematol 2018). Notably, prior work showed that 5 fractions of pancreas stereotactic radiation therapy (SBRT) resulted in less lymphopenia and an improved overall survival (OS) than chemoradiation (CRT) given over 5-6 weeks (Wild A, et al.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
The objective of the current study is to investigate the impact of the timing of immunotherapy with chemotherapy and radiation therapy (RT) on the overall survival (OS) of PDAC patients who did not receive surgical resection of the pancreatic tumor.Materials and Methods: Patients with pancreatic adenocarcinoma who did not receive surgical resection of the pancreatic tumor were identified from the National Cancer Database (NCDB). Cox proportional hazard models were employed to compare the OS between patients who received immunotherapy with chemotherapy or RT with a different sequence of treatment. The multivariable analysis...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
One-third of patients with pancreatic cancer has unresectable locally advanced disease at the time of diagnosis, and current treatment for these patients consists of a combination of chemotherapy and radiation therapy [1,2]. Historically, gemcitabine has been used as first-line chemotherapy after a pivotal multi-institutional trial showed both substantial clinical benefit and modestly improved survival with gemcitabine compared to 5-fluorouracil [3]. Recently, multiagent chemotherapy regimens have shown significant promise [4-7].
Source: Radiotherapy and Oncology - Category: Radiology Authors: Tags: Original Article Source Type: research
Opinion statementPatients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) should receive preoperative chemotherapy with or without radiation therapy, with the intent to eradicate occult metastatic cancer cells, to select patients with a “locally dominant cancer phenotype” for whom local therapies might be most effective, and to reduce the anatomic extent of tumors to facilitate surgical resection. The administration of preoperative therapy may also be a useful strategy to deliver the maximum load of chemotherapy to patients wit h BR PDAC, since as many as half of patients will never qualif...
Source: Current Treatment Options in Oncology - Category: Cancer & Oncology Source Type: research
Conditions:   Borderline Resectable Pancreatic Adenocarcinoma;   Locally Advanced Pancreatic Ductal Adenocarcinoma;   Resectable Pancreatic Ductal Adenocarcinoma;   Stage III Pancreatic Cancer AJCC v8 Interventions:   Other: Hafnium Oxide-containing Nanoparticles NBTXR3;   Radiation: Radiation Therapy Sponsors:   M.D. Anderson Cancer Center;   National Cancer Institute (NCI) Recruiting
Source: - Category: Research Source Type: clinical trials
Conclusions: PET imaging studies with [89Zr]Zr-DFO-anti-γH2AX-TAT following α- and β-particle PRIT in a BxPC3 PDAC subcutaneous xenograft mouse model allowed the monitoring of tumor radiobiological response to treatment.
Source: Theranostics - Category: Molecular Biology Authors: Tags: Research Paper Source Type: research
This study aims to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using Cyber Knife (CK) in the treatment of patients with recurrent pancreatic cancer after surgery, and analyze its survival-related factors. METHODS: The primary endpoint was freedom from local progression (FFLP) and local control (LC) rate after CK. The secondary endpoints were overall survival (OS), progression-free survival (PFS), symptom relief and toxicities. Receiver operating characteristic (ROC) curves were used to determine the optimal cut-off values of inflammatory composite indicators NLR, PLR, SII and PNI. Th...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research
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