Gene Expression Comparison Between the Lymph Node-Positive and Negative Reveals a Peculiar Immune-microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

Abstract

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene-expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window.To this end, we provide an original bioinformatic dissection of the gene-expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune-microenvironment identify subjects with nodal involvement.In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939, a specific WNT pathway inhibitor, has in re-educating a tumour permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in nodes-positive disease.

Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib

“…37 Moreover, Argentiero et al reported that Angiopoietin-like 4 (ANGPTL4), which is involved in regulation of immune homeostasis, modulating inflammatory T cell response, and expression of several cytokines, such as IL10 and IL1, was related to angiogenesis and tumor migration via α5β1integrin/RAC1 interaction in pancreatic cancer. 38 These findings suggest that angiogenesis factors have a beneficial role in survival, growth, or spread of cancer. Therefore, anti-angiogenic agents such as lenvatinib are expected to be particularly effective in patients in whom angiogenesis is upregulated.…”

The Neutrophil-to-Monocyte Ratio and Platelet-to-White Blood Cell Ratio Represent Novel Prognostic Markers in Patients with Pancreatic Cancer

“…Activation of oncogenes or inactivation of tumor suppressor genes can lead to transcription of inflammatory mediators, producing tumor-associated inflammatory microenvironment in the body [11]. The activation of the WNT and WNT2 pathway rendered a peculiar immune microenvironment in the lymph node positive for pancreatic ductal adenocarcinoma that promotes invasiveness, epithelial mesenchymal transition, and metastatic potential [12]. Myeloid-derived suppressor cells (MDSCs), one of the major cell populations comprised of macrophages, dendritic cells (DCs), and granulocytes, strongly expand in pathological situations such as cancer.…”

Clinical characteristics and surgical treatment of spinal metastases from pancreatic cancer: a single-center retrospective study

“…It is worth noting that zoledronic acid appears to modulate innate immunity by acting on tumor-associated macrophages. In addition, Argentiero and coworkers documented that the new immunotherapy strategy targeting the Wnt pathway can enhance the cytotoxicity of pancreatic cancer cells and restore antitumor immunity in lymph node-positive patients (35). Tumorstromal interactions are important for the progression of PDAC, and mast cells play a crucial role in the resistance to gemcitabine/paclitaxel treatment (36,37).…”