Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

Proteomic mapping and optogenetic manipulation of membrane contact sites.

Membrane contact sites (MCSs) mediate crucial physiological processes in eukaryotic cells, including ion signaling, lipid metabolism, and autophagy. Dysregulation of MCSs is closely related to various diseases, such as type 2 diabetes mellitus (T2DM), neurodegenerative diseases, and cancers. Visualization, proteomic mapping and manipulation of MCSs may help the dissection of the physiology and pathology MCSs. Recent technical advances have enabled better understanding of the dynamics and functions of MCSs. Here we present a summary of currently known functions of MCSs, with a focus on optical approaches to visualize and manipulate MCSs, as well as proteomic mapping within MCSs.

Identification of a STIM1 Splicing Variant that Promotes Glioblastoma Growth.

Deregulated store-operated calcium entry (SOCE) mediated by aberrant STIM1-ORAI1 signaling is closely implicated in cancer initiation and progression. Here the authors report the identification of an alternatively spliced variant of STIM1, designated STIM1ß, that harbors an extra exon to encode 31 additional amino acids in the cytoplasmic domain. STIM1ß, highly conserved in mammals, is aberrantly upregulated in glioma tissues to perturb Ca2+ signaling. At the molecular level, the 31-residue insertion destabilizes STIM1ß by perturbing its cytosolic inhibitory domain and accelerating its activation kinetics to efficiently engage and gate ORAI calcium channels. Functionally, STIM1ß depletion affects SOCE in glioblastoma cells, suppresses tumor cell proliferation and growth both in vitro and in vivo. Collectively, their study establishes a splicing variant-specific tumor-promoting role of STIM1ß that can be potentially targeted for glioblastoma intervention.

Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer.

Store-operated Ca2+ entry (SOCE) is the major pathway of Ca2+ entry in mammalian cells, and regulates a variety of cellular functions including proliferation, motility, apoptosis, and death. Accumulating evidence has indicated that augmented SOCE is related to the generation and development of cancer, including tumor formation, proliferation, angiogenesis, metastasis, and antitumor immunity. Therefore, the development of compounds targeting SOCE has been proposed as a potential and effective strategy for use in cancer therapy. In this review, we summarize the current research on SOCE inhibitors and blockers, discuss their effects and possible mechanisms of action in cancer therapy, and induce a new perspective on the treatment of cancer.

PEGylated hyaluronidase/NIR induced drug controlled release system for synergetic chemo-photothermal therapy of hepatocellular carcinoma.

In recent years, cancer treatment has been facing the challenge of increasing antitumor efficiency and avoiding severe adverse effects simultaneously. In this study, we designed a controlled release drug delivery system, doxorubicin (Dox)-loaded and hyaluronic acid (HA)-modified PEGylated gold nanocages (AuNCs), which was designated as PEG-HAn-AuNCs/Dox (n represented 10n HA repeating units were modified on each AuNC). In this system, AuNCs were applied as the photothermal cores, Dox was employed as the model drug, HA was applied as the tumor-microenvironment responsive switch to achieve controlled release, and poly (ethylene glycol) (PEG) was used as the stealth polymer to prolong systemic circulation time. Firstly, we evaluated the physical and chemical properties of the PEG-HAn-AuNCs/Dox with different ratios of HA to AuNC and found that PEG-HA4-AuNCs/Dox was the optimal. Secondly, PEG-HA4-AuNCs/Dox revealed the feature of controlled release, namely, the drug release was triggered by hyaluronidase (HAase) and accelerated by the acidic pH and near-infrared (NIR) irradiation. And then PEG-HA4-AuNCs/Dox could be effectively delivered to a cultured SMMC-7721 cell line in vitro and the tumor tissues of the subcutaneous mouse models of hepatocellular carcinoma (HCC) in vivo. Finally, the results demonstrated the synergetic therapy, namely the combination of chemotherapy and photothermal therapy (PTT) (defined as chemo-photothermal therapy) mediated by PEG-HA4-AuNCs/Dox, could efficiently inhibit the tumor growth both in vitro and in vivo. Therefore, the advantages of PEG-HA4-AuNCs/Dox endowed it as a great potential candidate for HCC treatment.

Prevention of gallstones by Lidan Granule: Insight into underlying mechanisms using a guinea pig model.

The aim of the study was to examine the mechanism of action of Lidan Granule (LDG) for the prevention of gallstones using a guinea pig model. One hundred guinea pigs were divided into five groups randomly: control (standard diet and saline), model [lithogenic diet (LD) and saline], LDG-H (LD and 2 g/kg of LDG), LDG-L (LD and 1 g/kg of LDG), and ursodeoxycholic acid (UDCA) (LD and UDCA) as the positive control. At 6 weeks, the rate of gallstone formation and weight of the adrenal gland were recorded and serum levels of inflammatory cytokines were measured. Levels of corticotrophin-releasing hormone (CRH) in the hypothalamus, adrenocorticotropic hormone (ACTH) in the hypophysis, and serum cortisol were determined. Bile components were tested with colorimetry. At 6 weeks, the rate of gallstone formation was significantly decreased in the LDG-H (14.29%) and LDG-L (21.43%) groups compared to the model group (81.25%; P<0.01). LDG treatment decreased the serum levels of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (P<0.01). LDG decreased bile cholesterol and increased bile acid and phospholipid levels in the bile (P<0.01). LDG treatment recovered the function of the hypothalamic-pituitary-adrenal (HPA) axis by increasing the expression of CRH (P<0.01) and ACTH (P<0.05). LDG made the bile less lithogenic, improved the function of the HPA axis, and regulated the expression of inflammatory cytokines for the prevention of cholelithiasis.

[Experimental study of apoptosis and proliferation of gastric mucosal cells in chronic atrophic gastritis].

OBJECTIVE: To study the relationship between long-term high-salt hot diet and chronic atrophic gastritis (CAG). The expression of apoptosis cells, proliferation cells, bcl-2 and Fas proteins were detected in the gastric mucosa of CAG rates induced by high-salt hot water. METHODS: TUNEL technique and immunohistochemical method were used in the experiment. Flow cytometry method was used to detect the DNA content of apoptosis cells. RESULTS: (1) The detection of apoptosis with TUNEL showed that the apoptosis cells in CAG rates induced by high-salt hot water were high. These cells could be seen in all layers of gastric mucosa, apoptosis index of model rates was higher than that of normal rates (P < 0.05). (2) The result of detecting apoptosis gene and proliferating cell nuclear antigen (PCNA) by immunohistochemical method showed that the expression of bcl-2, Fas and PCNA in the CAG rates induced by high-salt hot water was much higher than that of normal gastric mucosa (P < 0.05). The expression rates of bcl-2, Fas proteins were higher with time going on. After being given high-salt hot water intragastrically for 4, 8, 12 weeks, the bcl-2 protein expression rates were 12.5%, 16.7%, 76.5%, the Fas protein expression rates were 18.7%, 22.2% and 64.7%. (3) Flow cytometry technique showed that there was a second G(0)/G(1) peek, which was apoptosis cells peak, but was not seen in the normal gastric mucosa. CONCLUSIONS: Abnormality of proliferation and apoptosis in gastric mucosa could be induced by high-salt hot water. bcl-2, Fas gene played an important role in this course.