Calcium signaling induces a partial EMT.

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.

Cerebrospinal fluid venous fistula causing spontaneous intracranial hypotension resulting in venous sinus thrombosis and coma.

Cerebrospinal fluid (CSF) fistulas have recently been recognized as a cause of spontaneous intracranial hypotension (SIH), predominantly presenting with headaches, especially positional headaches. Atypical presentations like tinnitus and cranial nerve symptoms have also been reported. SIH has been linked to venous sinus thrombosis; however, to our knowledge, no prior cases describe a CSF venous fistula causing SIH that leads to cerebral venous thrombosis and coma. We report a patient who developed progressive venous sinus thrombosis, leading to coma, and was found to have low intracranial pressure indicative of SIH. Invasive monitoring and imaging confirmed the low intracranial pressure, prompting a dynamic myelogram that revealed a T2/3 CSF venous fistula. The patient underwent transvenous embolization of the fistula, which resulted in the resolution of symptoms and almost immediate improvement in both venous thrombosis and intracranial hypotension. CSF venous fistulae as a cause of SIH is a recently recognized entity, with ongoing research into its treatment through transvenous embolization. Most documented cases focus on patients with headaches. This case highlights a novel presentation, emphasizing the importance of thorough diagnostic workup in patients with cerebral venous thrombosis. Early detection and treatment of this condition can lead to significant clinical improvement, including the resolution of coma.

Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer.

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. SIGNIFICANCE: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.