A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis.

Cysteine substitutants emerge in lung cancer proteomes during arginine restriction.

In this issue of Molecular Cell, Yang et al. find that arginine-to-cysteine substitutants are enriched in a subset of lung cancer proteomes, potentiated by arginine deprivation, and promote resistance to chemotherapy.

Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine.

mutations are common driver oncogenes associated with the development of several solid tumors. oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state.

A Meta-Analysis to Assess the Efficacy of HER2-Targeted Treatment Regimens in HER2-Positive Metastatic Colorectal Cancer (mCRC).

Recent trials provide evidence that HER2 is a potential new target for patients with colorectal cancer. While HER2-positive tumors do not show a very encouraging response to anti-HER2-positive agents like trastuzumab alone, promising results have been observed when combined with other synergistically acting tyrosine kinase inhibitors (TKIs). Our meta-analysis was conducted following the Cochrane Handbook and written following the PRISMA guidelines.

Neoadjuvant Immune Checkpoint Inhibitor Therapy for Patients With Microsatellite Instability-High Colorectal Cancer: Shedding Light on the Future.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair-deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC.

Arginine limitation causes a directed DNA sequence evolution response in colorectal cancer cells.

Utilization of specific codons varies significantly across organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons.

Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons.

Two isoleucyl tRNAs that decode synonymous codons divergently regulate breast cancer metastatic growth by controlling translation of proliferation-regulating genes.

The human genome contains 61 codons encoding 20 amino acids. Synonymous codons representing a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression.

A G-quadruplex stabilizer, CX-5461 combined with two immune checkpoint inhibitors enhances in vivo therapeutic efficacy by increasing PD-L1 expression in colorectal cancer.

Purpose: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration.

Results: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells.

Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance.

Background: Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed.

Once bitten, twice shy: The negative spillover effect of seeing betrayal of trust.

From financial improprieties to fraudulent claims, scandals and trust transgressions can incite feelings of betrayal. Can these negative reactions spillover and taint other entities that were not involved in the original transgression? We conducted six studies to investigate this question directly. Results consistently demonstrated that people who had perceived a recent betrayal by a transgressing trustee were significantly less likely to trust a new entity that shared nominal group membership with the previous trust transgressor.

In silico modeling of combination systemic therapy for advanced renal cell carcinoma.

Therapeutic combinations of VEGFR tyrosine kinase inhibitor plus immune checkpoint blockade now represent a standard in the first-line management of patients with advanced renal cell carcinoma. Tumor molecular profiling has shown notable heterogeneity when it comes to activation states of relevant pathways, and it is not clear that concurrent pursuit of two mechanisms of action is needed in all patients. Here, we applied an in silico drug model to simulate combination therapy by integrating previously reported findings from individual monotherapy studies.

Wish-making during the COVID-19 pandemic enhances positive appraisals and job satisfaction.

Guided by cognitive appraisal theory, we argue that wish-making is a conceptually distinct type of coping strategy and that wish-making during the COVID-19 pandemic has functional cognitive-affective consequences. Specifically, it facilitates positive appraisals of the pandemic, which then facilitate job satisfaction. Enhanced job satisfaction in turn reduces counterproductive work behavior during the pandemic.

Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway.

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required.

From slacktivism to activism: Improving the commitment power of e-pledges for prosocial causes.

Prosocial organizations increasingly rely on e-pledges to promote their causes and secure commitment. Yet their effectiveness is controversial. Epitomized by UNICEF's "Likes Don't Save Lives" campaign, the threat of slacktivism has led some organizations to forsake social media as a potential platform for garnering commitment.

: new biomarker and drug target for checkpoint blockade immunotherapy.

Background: Immunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings.

Methods: Mutations in patients who responded to immunotherapy were identified through next-generation sequencing.

Changes in perceptions of ethical leadership: Effects on associative and dissociative outcomes.

From employees' point of view, changes in ethical leadership perceptions can signal important changes in the nature of the employment relationship. Guided by social exchange theory, this study proposes that changes in ethical leadership perceptions shape how employees appraise their exchange relationship with the organization and affect their pride in or contempt for the organization. Changes in these associative/dissociative emotions, in turn, precipitate changes in behaviors that serve or hurt the organization, notably voice and turnover.

Author Correction: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.

In the version of Supplementary Fig. 3c originally published with this Article, the authors mistakenly duplicated a blot from Supplementary Fig. 3b.

Snail-induced claudin-11 prompts collective migration for tumour progression.

Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms.

Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer.

In head and neck squamous cell carcinoma (HNSCC), the incidence of mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation-mediated resistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC. We used the -selected and -selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab.

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9.

The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo.

Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages.

Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation.

Development of siRNA payloads to target KRAS-mutant cancer.

Unlabelled: RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional "Sensor" assay to establish a library of potent siRNAs against RAS pathway genes and to show that they efficiently suppress their targets at low dose.