The transcriptional co-activators of the Hippo pathway, YAP and TAZ, are regulated by mechanotransduction, which depends on dynamic actin cytoskeleton remodeling. Here, we identified SEPTIN10 as a novel cytoskeletal protein, which is transcriptionally regulated by YAP/TAZ and whose overexpression correlates with poor survival and vascular invasion in hepatocellular carcinoma (HCC) patients. Functional characterization demonstrated that SEPTIN10 promotes YAP/TAZ-dependent cell viability, migration and invasion of liver cancer cells. Mechanistically, SEPTIN10 interacts with actin and microtubule filaments supporting actin stress fiber formation and intracellular tension through binding to CAPZA2 while concurrently inhibiting microtubule polymerization through the blockage of MAP4 function. This functional antagonism is important for cytoskeleton-dependent feedback activation of YAP/TAZ, as microtubule depolymerization induces actin stress fiber formation and subsequently YAP/TAZ activity. Importantly, the crosstalk between microfilaments and microtubules is mediated by SEPTIN10 as its loss abrogates actin stress fiber formation after microtubule disruption. Together, the YAP/TAZ target gene SEPTIN10 controls the dynamic interplay between actin and microtubule filaments, which feeds back on Hippo pathway activity in HCC cells and thus acts as molecular switch with impact on oncogenic signaling and cancer cell biology.

The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in liver cancer cells. The combination of proteomics and functional screening identified numerous apical cell polarity complex proteins interacting with YAP and TAZ. Co-immunoprecipitation (Co-IP) experiments confirmed that membrane protein palmitoylated 5 (MPP5; synonym: PALS1) physically interacts with YAP and TAZ. After removing different MPP5 protein domains, Co-IP analyses revealed that the PDZ domain plays a crucial role in YAP binding. The interaction between YAP and MPP5 in the cytoplasm of cancer cells was demonstrated by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, a reduction in apical MPP5 expression was observed, correlating with the nuclear accumulation of YAP and TAZ. Expression data analysis illustrated that MPP5 is inversely associated with YAP/TAZ target gene signatures in human HCCs. Low MPP5 levels define an HCC patient group with a poor clinical outcome. In summary, MPP5 facilitates the nuclear exclusion of YAP and TAZ in liver cancer. This qualifies MPP5 as a potential tumor-suppressor gene and explains how changes in cell polarity can foster tumorigenesis.

Background: Medical mistrust is a barrier to optimal cancer care. Analyzing social media posts where patients voice mistrust provides an opportunity to understand its variations and derive potential ways to address medical mistrust.Aims: To (1) identify the frequency of mistrust expression in cancer‐related Reddit posts, (2) characterize mistrusted entities and reasons for mistrust, and (3) identify emotional tone associated with mistrust.Methods: 101,963 posts from 10 entity‐specific cancer communities on the social media platform Reddit made before September 30, 2024, were analyzed using a Large Language Model (LLM, “gpt‐4o‐mini”) in this cross‐sectional study. Performance of the LLM was compared to human raters. Categories for mistrusted entities and reasons for mistrust were developed inductively by human evaluators. Subsequently, posts were assigned to these different categories by the LLM.Results: Of n = 101,963 posts analyzed, 19,159 posts (18.8%) were categorized as expressing mistrust, predominantly directed at healthcare professionals (n = 14,221, 74.2%). Most common reasons for mistrust were “disregard for patient concerns” (n = 8176, 42.7%), “perceived incompetence of medical management” (n = 4871, 25.4%), and problems in “communication” (n = 4060, 21.2%). Mistrust posts commonly contained “worried” (n = 5933, 31.0%), “concerned” (n = 3623, 18.9%) and “frustrated” (n = 3046, 15.9%) tones.Conclusions: Expression of medical mistrust is prevalent in social media and is predominantly directed at healthcare professionals. Mistrust is frequently associated with dismissal of patients' symptoms or concerns, a perceived lack of thoroughness in clinical management and communication difficulties, suggesting these as key actionable areas to address medical mistrust in clinical practice.