Negaar Goudarzi

Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by a striking tropism for epithelial tissues, particularly the salivary and lacrimal glands. Lack of function of the salivary glands (SGs) leads to a panoply of symptoms, dramatically reducing patient quality of life. Over the past decades, research has established that the ductal epithelium is not merely a structural component but rather a central player in the immunopathology of the SG in SjD. The aim of this review is to briefly reassess the evidence supporting the role of SG epithelium in the pathogenesis of the disease and to highlight how the development of new epithelial models of the salivary glands, namely organoids, may pave the way for novel research avenues and personalized therapeutic strategies.

Abstract Background: How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRASG12 (G12C or G12D) but specific outcomes of these subgroups of patients is poorly described. We analyzed clinical/genomic characteristics, and outcomes of PDAC depending on codon-specific KRAS (G12 vs others), as well as gene expression profiles and in vitro drug sensibility using organoids (PDO). Methods: All metastatic patients with PDAC and available molecular profile from 2015-2022 were eligible and patients with KRAS mutation were included (NCT0493252) in a monocentric retrospective cohort. A cohort of PDO was used to assess the efficacy of 25 antitumor therapies (chemogram) and transcriptomic data from 69 KRAS-mutated tumors was also analyzed. Results: Overall, 263 patients were included, 238 KRASG12 (91%) and 24 (9%) KRASother. There was no difference between KRASG12 and KRASother regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRASother (p=0.01). GNAS was found more altered in KRASother tumors (p=0.002) suggesting potential TIPMP precursors. Median overall survival from metastatic diagnosis was 16.7 months (95%CI:14.3-18.3) in KRASG12 and 24.9 months (95% CI:17.4-43.4) in KRASother (HR (ref:KRASG12)=0.56 (0.34-0.94), p=0.03 adjusted). First-line treatment-response was not different between groups (ORR and PFS), as confirmed with a similar PDO in vitro sensibility. Transcriptomic analyses showed a significant and exclusive upregulation of immune pathways in KRASG12 tumors. Conclusion: Codon-specific KRAS mutations are not equal and we report for the first time that KRASG12 patients have a worst prognosis than KRASother patients in PDAC. KRASG12 appears as a prognostic factor, as confirmed by transcriptomic analyses. These results warrant to be confirmed in larger scale studies. Citation Format: Alice Boilève, Adrien Rousseau, Marc Hilmi, Anthony Tarabay, Jacques R.R. Mathieu, Negaar Goudarzi, Jérôme Cartry, Sabrina Bedja, Claudio Nicotra, Maud NgoCamus, Valérie Boige, Marine Valéry, Mohamed Amine Bani, Lambros Tselikas, Antoine Italiano, Fanny Jaulin, Cristina Smolenschi, Antoine Hollebecque, Michel Ducreux. Codon-specific KRAS mutations predict survival in advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A101.

• Organoids are emerging tridimensional culture models established from stem cells that aim to mimic organ structure and function. • Organoid models are numerous, allowing promising applications: disease modelling, regenerative medicine and drug screening. • The development of organoids is an alternative to animal experimentation, but raises newly scientific, technical and ethical challenges. • This emerging tool offers promising prospects for the study of rheumatic diseases Organoids are three-dimensional (3D) culture models developed from stem cells that aim to mimic both organ structure and functions. This technique is developing in the field of translational research, emerging as a key model through its multiple applications. Numerous models have been developed from various organs, allowing disease modelling, drug screening and hopes in regenerative medicine. First developments in the field of rheumatic diseases have been made notably in osteoarthritis, rheumatoid arthritis and Sjögren disease. In this review, we will focus on the establishment of organoid culture and the development and potential applications of 3D culture in rheumatic diseases.