The 3.0 Cell Communication: New Insights in the Usefulness of Tunneling Nanotubes for Glioblastoma Treatment

Glioblastoma (GBM) is a particularly challenging brain tumor characterized by a heterogeneous, complex, and multicellular microenvironment, which represents a strategic network for treatment escape. Furthermore, the presence of GBM stem cells (GSCs) seems to contribute to GBM recurrence after surgery, and chemo- and/or radiotherapy. In this context, intercellular communication modalities play key roles in driving GBM therapy resistance. The presence of tunneling nanotubes (TNTs), long membranous open-ended channels connecting distant cells, has been observed in several types of cancer, where they emerge to steer a more malignant phenotype. Here, we discuss the current knowledge about the formation of TNTs between different cellular types in the GBM microenvironment and their potential role in tumor progression and recurrence. Particularly, we highlight two prospective strategies targeting TNTs as possible therapeutics: (i) the inhibition of TNT formation and (ii) a boost in drug delivery between cells through these channels. The latter may require future studies to design drug delivery systems that are exchangeable through TNTs, thus allowing for access to distant tumor niches that are involved in tumor immune escape, maintenance of GSC plasticity, and increases in metastatic potential.

New Approaches in Characterization of Lesions Dissemination in DLBCL Patients on Baseline PET/CT

Dissemination, expressed recently by the largest Euclidian distance between lymphoma sites (SDmax), appeared a promising risk factor in DLBCL patients. We investigated alternative distance metrics to characterize the robustness of the dissemination information. In 290 patients from the REMARC trial (NCT01122472), the Euclidean (Euc), Manhattan (Man), and Tchebychev (Tch) distances between the furthest lesions, firstly based on the centroid of each lesion and then directly from the two most distant tumor voxels and the Travelling Salesman Problem distance (TSP) were calculated. For PFS, the areas under the ROC curves were between 0.63 and 0.64, and between 0.62 and 0.65 for OS. Patients with high SDmax whatever the method of calculation or high SD_TSP had a significantly poorer outcome than patients with low SDmax or SD_TSP (p < 0.001 for both PFS and OS), with significance maintained in Ann Arbor advanced-stage patients. In multivariate analysis with total metabolic tumor volume and ECOG, each distance feature had an independent prognostic value for PFS. For OS, only SDmax_Tch, SDmax_Euc _Vox, and SDmax_Man _Vox reached significance. The spread of DLBCL lesions measured by the largest distance between lymphoma sites is a strong independent prognostic factor and could be measured directly from tumor voxels, allowing its development in the area of the deep learning segmentation methods.

Paraneoplastic neurological syndrome: an evolving story

Paraneoplastic neurological syndrome (PNS) comprises a group of neurological disorders that result from a misguided immune response to the nervous system triggered by a distant tumor. These disorders frequently manifest before the diagnosis of the underlying neoplasm. Since the first reported case in 1888 by Oppenheim, the knowledge in this area has evolved rapidly. Several classic PNS have been described, such as limbic encephalitis, paraneoplastic cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus, sensory neuronopathy, Lambert-Eaton Myasthenic syndrome, and chronic gastrointestinal dysmotility. It is now recognized that PNS can have varied nonclassical manifestations that extend beyond the traditional syndromic descriptions. Multiple onconeural antibodies with high specificity for certain tumor types and neurological phenotypes have been discovered over the past 3 decades. Increasing use of immune checkpoint inhibitors (ICIs) has led to increased recognition of neurologic ICI-related adverse events. Some of these resemble PNS. In this article, we review the clinical, oncologic, and immunopathogenic associations of PNS.

Association of CD44−/CD24− Breast Cancer Cells with Late Stage Tumor Recurrence

Tumor metastasis remains the main cause of breast cancer-related deaths, especially the later breast cancer distant metastasis. This study assessed CD44−/CD24− tumor cells in 576 tissue specimens for associations with clinicopathological features and metastasis and then investigated the underlying molecular events. The data showed that level of CD44−/CD24− cells was associated with later postoperative distant tumor metastasis. Furthermore, CD44−/CD24− triple negative cells could spontaneously convert into CD44+/CD24− cancer stem cells (CSCs) with properties similar to CD44+/CD24− CSCs from parental MDA-MB-231 cells in terms of gene expression, tumor cell xenograft formation, and lung metastasis in vitro and in vivo. Single-cell RNA sequencing identified RHBDL2 as a regulator that enhanced spontaneous CD44+/CD24− CSC conversion, whereas knockdown of RHBDL2 expression inhibited YAP/NF-κB signaling and blocked spontaneous CD44−/CD24− cell conversion to CSCs. These data suggested that the level of CD44−/CD24− tumor cells could predict breast cancer prognosis, metastasis, and response to adjuvant therapy.