Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma

In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.Fil: Molejon, Maria Ines. Institut National de la Santé et de la Recherche Médicale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; ArgentinaFil: Swayden, Mirna. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Fanale, Daniele. 3 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.; Argentina. University of Palermo. Department of Surgical, Oncological and Oral Sciences; ItaliaFil: Bintz, Jennifer. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Gayet, Odile. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Soubeyran, Philippe. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Iovanna, Juan Lucio. Institut National de la Santé et de la Recherche Médicale; Franci

Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. Patients and Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients' overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis

Keeping Time: Implementing Appointment-based Family-centered Rounds.

Background:Family-centered rounds (FCRs) provide many benefits over traditional rounds, including higher patient satisfaction, and shared mental models among staff. These benefits can only be achieved when key members of the care team are present and engaged. We aimed to improve patient engagement and satisfaction with our existing bedside rounds by designing a new FCR process. Methods:We conducted a needs assessment and formed a multidisciplinary FCR committee that identified appointment-based family-centered rounds (aFCRs) as a primary intervention. We designed, implemented, and iteratively refined an aFCR process. We tracked process metrics (rounds attendance by key participants), a balancing metric (time per patient), and outcome metrics (patient satisfaction domains) during the intervention and follow-up periods. Results:After implementing aFCR, 65% of patients reported positive experience with rounds and communication. Rounds duration per patient was similar (9 versus 9.4 min). Nurse, subspecialist, and interpreter attendance on rounds was 72%, 60%, and 90%, respectively. We employed a Rounding Coordinator to complete the scheduling and communication required for successful aFCR. Discussion:We successfully improved our rounding processes through the introduction of aFCR with the addition of a rounding coordinator. Our experience demonstrates one method to increase multidisciplinary team member attendance on rounds and patient satisfaction with physician communication in the inpatient setting

ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR

Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy

The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of these cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment. In this review, we discuss the non-genetic mechanisms that eventually result in cancer resistance to targeted therapies, with a special focus on those involving changes in gene expression

Role of ubiquitin family dependent post-translational modifications in the resistance mechanisms of pancreatic cancer cells : identification and validation of new therapeutic targets

Le pronostic sombre de l'adénocarcinome pancréatique est principalement dû à la résistance rapidement acquise à tous les traitements conventionnels. Malgré les mécanismes de résistance spécifiques aux médicaments, aucun n’explique comment ces cellules résistent à tous types de stress induit par tous types de traitements anticancéreux. L'activation des voies de réponse au stress repose sur les modifications post-traductionnelles (PTM) des protéines impliquées. Parmi toutes les PTMs, celles médiées par la famille de protéines ubiquitine jouent un rôle central dans le processus. Notre objectif était d'identifier les altérations de l'ubiquitination, de la neddylation et de la sumoylation associées au phénotype multi-résistant et de démontrer leur implication dans la survie des cellules cancéreuse pancréatique en cours de traitement. Cette approche a mis en évidence une modification de la sumoylation de la protéine PML (Promyelocytic leukemia) associée à la résistance à la gemcitabine et à l'oxaliplatine. Nous avons montré que cette altération de la sumoylation de PML fait partie d'un mécanisme général de résistance aux traitements, qui implique en outre l'activation anormale des voies NFkB et CREB. De manière importante, en utilisant des tumeurs et lignées cellulaires dérivées de patients, nous avons identifié une corrélation entre les niveaux d’expression et de sumoylation de PML avec la sensibilité des tumeurs aux traitements anticancéreux et la survie des patients.The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is mainly due to the rapidly acquired resistance to all conventional treatments. Despite drug specific mechanisms of resistance, none explains how these cells resist to any kind of stress induced by any kind of anticancer treatment. Activation of stress response pathways rely on the post-translational modifications (PTMs) of involved proteins. Among all PTMs, these mediated by the ubiquitin family of proteins play a central role in process. Our aim was to identify alterations of ubiquitination, neddylation, and sumoylation associated with multi-resistant phenotype and demonstrate their implication in survival of PDAC cells undergoing treatment. This approach pointed out an alteration of PML (Promyelocytic Leukemia protein) sumoylation associated with both Gemcitabine and Oxaliplatin resistance. We could show that this alteration of PML sumoylation is part of a general mechanism of drug resistance, which, in addition, involves the abnormal activation of NFkB and CREB pathways. Importantly, using patients derived tumors and cell lines; we identified a correlation between the levels of PML expression and sumoylation with the sensitivity of tumors to anticancer treatments and patient’s survival

Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest forms of cancer. A major reason for this situation is the fact that these tumors are already resistant or become rapidly resistant to all conventional therapies. Like any transformation process, initiation and development of PDCA are driven by a well known panel of genetic alterations, few of them are shared with most cancers, but many mutations are specific to PDAC and are partially responsible for the great inter-tumor heterogeneity. Importantly, this knowledge has been inefficient in predicting response to anticancer therapy, or in establishing diagnosis and prognosis. Hence, the pre-existing or rapidly acquired resistance of pancreatic cancer cells to therapeutic drugs rely on other parameters and features developed by the cells and/or the micro-environment, that are independent of their genetic profiles. This review sheds light on all major phenotypic, non genetic, alterations known to play important roles in PDAC cells resistance to treatments and therapeutic escape