Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC.

The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2− ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care.

Introduction: Damage specific DNA binding protein 2 (DDB2) is an UV-indiced DNA damage recognition factor and regulator of cancer development and progression. DDB2 has dual roles in several cancers, either as an oncogene or as a tumor suppressor gene, depending on cancer localization. Here, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC). Methods: The expression level of DDB2 in pancreatic cancer tissues and its correlation with patient survival were evaluated using publicly available data. Two PDAC cell models with CRISPR-modified DDB2 expression were developed: DDB2 was repressed in DDB2-high T3M4 cells (T3M4 DDB2-low) while DDB2 was overexpressed in DDB2-low Capan-2 cells (Capan-2 DDB2-high). Immunofluorescence and qPCR assays were used to investigate epithelial-to-mesenchymal transition (EMT) in these models. Migration and invasion properties of the cells were also determined using wound healing and transwell assays. Sensitivity to 5-fluorouracil (5-FU), oxaliplatin, irinotecan and gemcitabine were finally investigated by crystal violet assays.Results: DDB2 expression level was reduced in PDAC tissues compared to normal ones and DDB2-low levels were correlated to shorter disease-free survival in PDAC patients. DDB2 overexpression increased expression of E-cadherin epithelial marker, and decreased levels of N-cadherin mesenchymal marker. Conversely, we observed opposite effects in DDB2 repression and enhanced transcription of SNAIL, ZEB1, and TWIST EMT transcription factors (EMT-TFs). Study of migration and invasion revealed that these properties were negatively correlated with DDB2 expression in both cell models. DDB2 overexpression sensitized cells to 5-fluorouracil, oxaliplatin and gemcitabine.Conclusion: Our study highlights the potential tumor suppressive effects of DDB2 on PDAC progression. DDB2 could thus represent a promising therapeutic target or biomarker for defining prognosis and predicting chemotherapy response in patients with PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Therapeutic options for PDAC are primarily restricted to surgery in the early stages of the disease or chemotherapy in advanced disease. Only a subset of patients with germline defects in BRCA1/2 genes can potentially benefit from personalized therapy, with the PARP inhibitor olaparib serving as a maintenance treatment for metastatic disease. Although the role of radiotherapy in PDAC remains controversial, the use of radiosensitizers offers hope for improving cancer management. Previously, we have shown that damage-specific DNA binding protein 2 (DDB2) is a potential prognostic and predictive biomarker for chemotherapy response in PDAC. In this study, we investigated the function of DDB2 in radiotherapy response, with and without radiosensitization by olaparib in PDAC cells. Our findings demonstrated DDB2 resistance to radiation effects, thereby improving cell survival and enhancing the repair of ionizing radiation-induced DNA double-strand breaks. We observed that DDB2 expression enhances the cell cycle arrest in the G2 phase by phosphorylating Chk1 and Chk2 cell cycle checkpoints. Additionally, we identified a novel link between DDB2 and PARP1 in the context of radiotherapy, which enhances the expression and activity of PARP1. Our findings highlight the potential of low-DDB2 expression to potentiate the radiosensitization effect of olaparib in PDAC cells. Collectively, this study provides novel insights into the impacts of DDB2 in the radiotherapy response in PDAC, enabling its employment as a potential biomarker to predict resistance to radiation. Furthermore, DDB2 represents a significant step forward in precision radiotherapy by widening the scope of patients who can be benefiting from olaparib as a radiosensitizer. Hence, this research has the potential to enrich the limited use of radiotherapy in the care of patients with PDAC.

Homologous recombination deficiency (HRD) affects 50% of ovarian cancers (OC) and influences PARP inhibitors efficacy. While one-third of HRD tumours harbour a deleterious BRCA1/2 mutation, these mutations are not the sole cause of HRD. Promoter methylation of BRCA1 and RAD51C contributes to 19% and 2% of cases, respectively. A cohort of 224 ovarian cancer (OC) patients tested for HRD validated our droplet digital PCR (ddPCR) technique. DNA was extracted from FFPE tissue, and the Genomic Instability Index (GII) was assessed using the Sophia DDM HRD Solution (Sophia Genetics). BRCA1 and RAD51C promoter methylation was analysed by ddPCR following enzymatic conversion, with a 10% threshold for methylation classification. Homologous recombination (HR) status was assessed in 194 patients. A positive GII (>0) was identified in 77 cases (39.7%), with 24 (31.2%) harbouring a deleterious BRCA1/2 mutation, and 2 (2.6%) a RAD51C mutation. Methylation analysis revealed BRCA1 promoter methylation in 32 patients (41.6%) and RAD51C promoter methylation in 1 patient (1.3%), clarifying HRD status in 28 additional cases (36.3%). Our study confirms HRD extends beyond BRCA1/2 mutations, with promoter methylation playing a significant role in HRD detection. ddPCR effectively identified methylation-driven HRD, explaining deficiency in 36.4% additional patients with a positive GII score. These findings highlight the importance of incorporating methylation analysis into HRD testing to improve patient stratification for PARP inhibitor therapy.