profiling-ubiquitin-ubiquitin-like-dependent-post-translational

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations

Ubiquitin (ub) and ubiquitin-like (ubl) dependent post-translational modifications of proteins play fundamental biological regulatory roles within the ...

Institut Paoli-Calmettes, CRCM

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  and . 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.

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

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.

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

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.

Article	Year
Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma. Oncotarget\| PubMed ID: 30112111	2018
Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype. Heliyon\| PubMed ID: 30582059	2018
Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma? Therapeutic advances in medical oncology\| PubMed ID: 31205506	2019

Mirna Swayden

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