Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity.

Understanding molecular mechanisms that dictate B cell diversity is important for targeting B cells as anti-cancer treatment. Through the single-cell dissection of B cell heterogeneity in longitudinal samples of patients with breast cancer before and after neoadjuvant chemotherapy, we revealed that an ICOSL+ B cell subset emerges after chemotherapy. Using three immunocompetent mouse models, we recapitulated the subset switch of human tumor-infiltrating B cells during chemotherapy. By employing B-cell-specific deletion mice, we showed that ICOSL in B cells boosts anti-tumor immunity by enhancing the effector to regulatory T cell ratio. The signature of ICOSL+ B cells is imprinted by complement-CR2 signaling, which is triggered by immunogenic cell death. Moreover, we identified that CD55, a complement inhibitory protein, determines the opposite roles of B cells in chemotherapy. Collectively, we demonstrated a critical role of the B cell subset switch in chemotherapy response, which has implications in designing novel anti-cancer therapies. VIDEO ABSTRACT.

CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness.

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

Influence of Physical Attractiveness and Gender on Patient Preferences in Digital Doctor Consultations: Experimental Study.

BACKGROUND: The rise of digital health services, particularly digital doctor consultations, has created a new paradigm in health care choice. While patients traditionally rely on digital reviews or referrals to select health care providers, the digital context often lacks such information, leading to reliance on visual cues such as profile pictures. Previous research has explored the impact of physical attractiveness in general service settings but is scant in the context of digital health care. OBJECTIVE: This study aims to fill the research gap by investigating how a health care provider's physical attractiveness influences patient preferences in a digital consultation setting. We also examine the moderating effects of disease severity and the availability of information on health care providers' qualifications. The study uses signal theory and the sexual attribution bias framework to understand these dynamics. METHODS: Three experimental studies were conducted to examine the influence of health care providers' physical attractiveness and gender on patient preferences in digital consultations. Study 1 (n=282) used a 2×2 between-subjects factorial design, manipulating doctor attractiveness and gender. Study 2 (n=158) focused on women doctors and manipulated disease severity and participant gender. Study 3 (n=150) replicated study 2 but added information about the providers' abilities. RESULTS: This research found that patients tend to choose attractive doctors of the opposite gender but are less likely to choose attractive doctors of the same gender. In addition, our studies revealed that such an effect is more prominent when the disease severity is high. Furthermore, the influence of gender stereotypes is mitigated in both the high and low disease severity conditions when service providers' qualification information is present. CONCLUSIONS: This research contributes to the literature on medical information systems research and sheds light on what information should be displayed on digital doctor consultation platforms. To counteract stereotype-based attractiveness biases, health care platforms should consider providing comprehensive qualification information alongside profile pictures.

Tumor promoter TPA activates Wnt/ß-catenin signaling in a casein kinase 1-dependent manner.

The tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/ß-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/ß-catenin signaling in mouse skin carcinogenesis. Here, we found that TPA could enhance Wnt/ß-catenin signaling in a casein kinase 1 (CK1) ε/δ-dependent manner. TPA stabilized CK1ε and enhanced its kinase activity. TPA further induced the phosphorylation of LRP6 at Thr1479 and Ser1490 and the formation of a CK1ε-LRP6-axin1 complex, leading to an increase in cytosolic ß-catenin. Moreover, TPA increased the association of ß-catenin with TCF4E in a CK1ε/δ-dependent way, resulting in the activation of Wnt target genes. Consistently, treatment with a selective CK1ε/δ inhibitor SR3029 suppressed TPA-induced skin tumor formation in vivo, probably through blocking Wnt/ß-catenin signaling. Taken together, our study has identified a pathway by which TPA activates Wnt/ß-catenin signaling.

CDDO-Me Elicits Anti-Breast Cancer Activity by Targeting LRP6 and FZD7 Receptor Complex.

Aberrant activation of the Wnt/ß-catenin pathway leads to the development of multiple cancers, including breast cancer. Development of therapeutic agents against this signaling pathway is an urgent need. In this study, we found that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) could inhibit Wnt/ß-catenin signaling mainly through targeting the low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed that CDDO-Me mediated the degradation of FZD7 in an LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and FZD7 and reduced the levels of phosphorylated Disheveled (DVL) 2 and active ß-catenin, resulting in the downregulation of Wnt target genes and several cancer stem cell (CSC) marker genes. In a murine xenograft bearing mouse mammary tumor virus (MMTV)-Wnt1-driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth and was accompanied by reduced expression of phosphorylated and total LRP6, phosphorylated and unphosphorylated DVL2, active ß-catenin, several Wnt target genes, and CSC marker genes. Collectively, the results of our study present that CDDO-Me is a potent Wnt/ß-catenin signaling inhibitor that may be a promising therapeutic agent against breast cancer. SIGNIFICANCE STATEMENT: Blocking the membrane receptor complex consisting of low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 may help developing therapeutic approaches for cancers, including breast cancers. Our study indicates that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) can inhibit Wnt/ß-catenin signaling by inducing the ubiquitination and degradation of LRP6/FZD7 membrane receptor complex via a lysosomal pathway. We also found that the ectodomain of LRP6 is essential for CDDO-Me-induced FZD7 degradation. Defining CDDO-Me as a novel inhibitor of Wnt/ß-catenin signaling, our results provide insight into the mechanism of its anticancer activity.

Prodigiosin inhibits Wnt/ß-catenin signaling and exerts anticancer activity in breast cancer cells.

Prodigiosin, a natural red pigment produced by numerous bacterial species, has exhibited promising anticancer activity; however, the molecular mechanisms of action of prodigiosin on malignant cells remain unclear. Aberrant activation of the Wnt/ß-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/ß-catenin pathway. Prodigiosin blocked Wnt/ß-catenin signaling by targeting multiple sites of this pathway, including the low-density lipoprotein-receptor-related protein (LRP) 6, Dishevelled (DVL), and glycogen synthase kinase-3ß (GSK3ß). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3ß and suppressed ß-catenin-stimulated Wnt target gene expression, including expression of cyclin D1. In MDA-MB-231 breast cancer xenografts and MMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3ß, active ß-catenin, and cyclin D1. Through its ability to inhibit Wnt/ß-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.

Gigantol inhibits Wnt/ß-catenin signaling and exhibits anticancer activity in breast cancer cells.

BACKGROUND: Gigantol is a bibenzyl compound derived from several medicinal orchids. This biologically active compound has been shown to have promising therapeutic potential against cancer cells, but its mechanism of action remains unclear. METHODS: The inhibitory effect of gigantol on Wnt/ß-catenin signaling was evaluated with the SuperTOPFlash reporter system. The levels of phosphorylated low-density lipoprotein receptor related protein 6 (LRP6), total LRP6 and cytosolic ß-catenin were determined by Western blot analysis. The expression of Wnt target genes was analyzed using real-time PCR. Cell viability was measured with a MTT assay. The effect of gigantol on cell migration was examined using scratch wound-healing and transwell migration assays. RESULTS: Gigantol decreased the level of phosphorylated LRP6 and cytosolic ß-catenin in HEK293 cells. In breast cancer MDA-MB-231 and MDA-MB-468 cells, treatment with gigantol reduced the level of phosphorylated LRP6, total LRP6 and cytosolic ß-catenin in a dose-dependent manner, resulting in a decrease in the expression of Wnt target genes Axin2 and Survivin. We further demonstrated that gigantol suppressed the viability and migratory capacity of breast cancer cells. CONCLUSION: Gigantol is a novel inhibitor of the Wnt/ß-catenin pathway. It inhibits Wnt/ß-catenin signaling through downregulation of phosphorylated LRP6 and cytosolic ß-catenin in breast cancer cells.

Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation.

Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid ß-Oxidation.

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid ß-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Using Humor to Promote Social Distancing on Tiktok During the COVID-19 Pandemic.

Background: During the COVID-19 pandemic, many humorous videos on how to practice social distancing appeared on social media. However, the effect of using humor as a crisis communication strategy to persuade people to conform to social distancing rules is not known. Objective: Drawing on the literature on humorous message framing and crisis communication, this research explores the effectiveness of a humorous message in communicating social distancing rules in two crisis severity phases (low vs. high severity) and also evaluates how humor affects individuals' online and offline engagement intentions during the COVID-19 pandemic. Methods: A 2 (message framing: humorous vs. non-humorous) x 2 (crisis severity phase: low vs. high) between-subjects design experiment was conducted to test the research questions during the first weeks of the COVID-19 pandemic in China from January 30 to February 2, 2020. Results: The results showed that the severity of the phase of a health crisis can significantly affect stakeholders' online and offline responses toward the disease. More specifically, in a low severity phase, humor led to increased source likability for the message, and more online and offline engagement intentions. However, no differences between a humorous and non-humorous message in perceived risk were observed. Whereas, in a high severity crisis phase, humor reduced individuals' offline engagement intentions and a decrease in perceived risk, no significant difference was found between a humorous and non-humorous message on source likeability. Conclusion: Humor can motivate both more online engagement and offline protective action intention when the crisis severity phase is low, while when crisis severity soars, a non-humorous message should be more desirable. More specifically, using humor in communicating information about an infectious disease can enhance the spokesperson's likeability in a low severity phase, and also helps to spread health information to a larger audience. While, the negative side of using humor in communicating an infectious disease appears in severe crisis phases, as it then decreased the public's perception of risk, and triggers less protective actions. Going beyond previous research, this study recognized that crisis severity changes in different phases of the spread of infectious disease, thereby providing actionable strategy selections for crisis practitioners in a dynamic communication environment.

Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.

Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.

Persuasive Effects of Message Framing and Narrative Format on Promoting COVID-19 Vaccination: A Study on Chinese College Students.

During a public health crisis, the provision and dissemination of health-related information are important for the relevant authorities to keep the public informed. By using different types of message framing, the authorities can effectively guide and persuade people to adopt health-related behaviors (such as vaccination). In this study, a web-based experiment using a 2 × 2 (message framing: gain framing versus loss framing) × (message presentation: narrative versus non-narrative) design was conducted to investigate the effects of different message frames on vaccination promotion. In total, 298 college students were recruited to participate in this study. The results suggest that, for message framing, loss-framed (vs. gain-framed) messages lead to higher intentions to get vaccinated. Furthermore, compared with non-narrative messages, narrative messages are more persuasive in promoting vaccination behavior. However, the interaction effect between gain-loss message framing and narrative framing is not significant. Additionally, perceived severity, perceived benefits, and perceived costs mediate the effect of narrative framing on behavioral intentions. In other words, compared with non-narrative messages, narrative messages lead to higher levels of perceived severity and perceived benefits, and a lower level of perceived costs, which in turn increase intentions to get vaccinated. This paper provides insightful implications for both researchers and practitioners.

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate-limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.

Salinomycin exerts anti-colorectal cancer activity by targeting the ß-catenin/T-cell factor complex.

BACKGROUND AND PURPOSE: Salinomycin is a well-known inhibitor of human cancer stem cells (CSCs). However, the molecular mechanism(s) by which salinomycin targets colorectal CSCs is poorly understood. Here, we have investigated underlying antitumour mechanisms of salinomycin in colorectal cancer cells and three tumour models. EXPERIMENTAL APPROACH: The inhibitory effect of salinomycin on the Wnt/ß-catenin pathway was analysed with the SuperTopFlash reporter system. The mRNA expression of Wnt target genes was evaluated with real-time PCR. Effects of salinomycin on ß-catenin/TCF4E interaction were examined using co-immunoprecipitation and an in vitro GST pull-down assay. Cell proliferation was determined by BrdU incorporation and soft agar colony formation assay. The stemness of the cells was assessed by sphere formation assay. Antitumour effects of salinomycin on colorectal cancers was evaluated with colorectal CSC xenografts, APCmin/+ transgenic mice, and patient-derived colorectal tumour xenografts. KEY RESULTS: Salinomycin blocked ß-catenin/TCF4E complex formation in colorectal cancer cells and in an in vitro GST pull-down assay, thus decreasing expression of Wnt target genes. Salinomycin also suppressed the transcriptional activity mediated by ß-catenin/LEF1 or ß-catenin/TCF4E complex and exhibited an inhibitory effect on the sphere formation, proliferation, and anchorage-independent growth of colorectal cancer cells. In colorectal tumour xenografts and APCmin/+ transgenic mice, administration of salinomycin significantly reduced tumour growth and the expression of CSC-related Wnt target genes including LGR5. CONCLUSIONS AND IMPLICATIONS: Our study suggested that salinomycin could suppress the growth of colorectal cancer by disrupting the ß-catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment.