Breast cancer cells that break through the basement membrane interact directly with neighboring adipocytes. Therefore, adipocytes adjacent to the invasive front of tumour undergo lipolysis and transform into cancer-associated adipocytes (CAAs), which is vital for the malignant progression of breast cancer. However, tumor-derived factors that trigger this process are still to be determined. Transcriptome sequencing was used to identify the downstream transcription factor of adrenomedullin (AM). Tet-On system was used to construct the 3T3-L1 cell line with inducible overexpression of Zeb1. Adipocyte-specific knock-in Zeb1 transgenic mice (Zeb1adiTG) were used to construct an allograft tumor model. Breast cancer cell-derived AM downregulated the transcriptional expression of Zeb1 by triggering the cAMP/PKA/Creb1 pathway, thereby exerting lipolytic effects in CAAs. On the contrary, adipose tissue-specific upregulation of Zeb1 significantly attenuated AM-induced lipolytic phenotypes. Of note, we used the Zeb1adiTG mice to construct allograft tumor models. The results confirmed that breast cancer cell-derived AM conferred tumorigenicity in vivo, which effect was predominantly dependent on the aberrant expression of adipocyte-specific Zeb1. These findings collectively suggested that breast cancer cell-derived AM promotes lipid metabolic reprogramming through a Zeb1-dependent manner in CAAs, which displays significant clinical implications and may provide promising therapeutic approaches for targeting the breast cancer-associated adipose microenvironment.

For patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations). Using state of the science mechanistic, metabolomic and spatial transcriptomic approaches combined with preclinical models of HNSCC, we tested whether a novel PI3K inhibitor, gedatolisib, can bypass hyperactivation of the Nrf2 pathway. The PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade, as demonstrated in an in vivo shRNA screen with platinum-based chemotherapy. Gedatolisib effectiveness appears mediated through activation of autophagy, G2/M arrest, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T-lymphocytes. These findings emphasize the critical role of the PI3K-AKT-mTOR pathway in chemo-radiation resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors in a disease that is refractory to all conventional therapeutic approaches.

Particulate matterwith a diameterof 2.5 micrometers or less (PM2.5) is a known lung carcinogen, but its impact in low-pollution settings is less understood. We assessed the association between long-term PM2.5 exposure and lung cancer risk in Northern Ireland (NI), a region with relatively low air pollution levels. We conducted a population-based case-control study using data from the Northern Ireland Cancer Registry and the Northern Ireland Cohort for the Longitudinal Study of Ageing. The study included 917 lung cancer cases diagnosed in 2014 and 8,088 controls without lung cancer. Eight-year average PM2.5 exposure was estimated by linking residential postcodes to 1 km² resolution pollution maps. Fully adjusted logistic regression models were used, controlling for key confounders including smoking status and deprivation index to estimate odds ratios (ORs) andtheir 95% confidence intervals (95% CI), and population attributable fractions (PAFs). Individuals in the highest PM2.5 tertile (>9.6 µg/m³) had a 37% increased lung cancer risk (OR: 1.37; 95% CI: 1.12-1.68) compared to the lowest tertile (<7.4 µg/m³). The association was stronger in women (OR: 1.79; 95% CI: 1.32-2.44) and not detected in men. Exposure above 10 µg/m³ accounted for 10% of cases, approximately 137 preventable lung cancers annually. Even in low-pollution regions, PM2.5 contributes to lung cancer risk, especially in women. Strengthened air quality measures are needed to reduce preventable disease.

Survival differences between socioeconomic groups in colorectal cancer have been studied for patients diagnosed in the 90s and 00s, but research on recent patients using individual measures of socioeconomic position is limited. CRCBaSe, a database of linked national registry data, was used to analyse stage I-III colorectal cancer patients diagnosed in Sweden between 2008 and 2021. The exposures of interest were income and education. Flexible parametric survival models were fitted and standardised survival probabilities and hazard ratios (HR) were calculated for cancer-specific survival, recurrence, and overall survival. Analysis of 59,995 patients showed better 5-year standardised cancer-specific survival in the least deprived income group, 77.8% (95%CI 76.9-78.6) vs. 73.2% (95%CI 72.6-73.9) in the most deprived income group, HR 0.93 (95%CI 0.87-0.99). Time to recurrence was not statistically different between socioeconomic groups. Overall survival was better in the least deprived income group, with a 5-year standardised overall survival of 70.0% (95%CI 69.1-70.8) vs. 63.5% (95%CI 62.9-64.1) in the most deprived income group, HR 0.82 (95%CI 0.79-0.86). We found large disparities in cancer-specific and overall survival between the highest and most deprived income and education groups, despite improvements in care and the introduction of guidelines.

pT3a renal cell carcinoma (RCC) encompasses three different types of progression features leading to persistent debate on prognostic heterogeneity and the need for reclassification. Data of 1606 patients with pT3aN0/xM0 RCC was analyzed according to the site of invasion (perinephric fat (PFI), sinus fat (SFI), renal vein (RVI), PFI and SFI without RVI (PFI + SFI), and both fat and vein (RVI + FI)) using Kaplan-Meier and Cox proportional hazards methods. RNA sequencing was performed on tumor samples from 19 SFI and 14 RVI patients to identify differentially expressed genes and pathway enrichments. Five-year DFS were 76%, 68.5%, 62.4%, 63.9%, and 50.1% for SFI, PFI, PFI + SFI, RVI and RVI + FI groups, respectively (p < 0.001). Vein invasion tumors demonstrating consistently poorer survival on size-stratified analysis. Site of invasion was an independent prognostic factor. Transcriptomic profiling revealed that SFI tumors were enriched for epithelial-mesenchymal transition, KRAS signaling, and extracellular matrix reprogramming, whereas RVI tumors exhibited hypoxia, oxidative phosphorylation, and DNA repair pathway activation. In T3a RCC, site of invasion was an independent prognosticator of survival regardless of tumor size. SFI and RVI tumors exhibited distinct genomic and pathway profiles suggesting an intrinsically disparate competencies directing the tumors to adopt different invasion mechanisms.

Existing epidemiological evidence regarding the potential role of (poly)phenol intake in lymphoma development is limited. We investigated the associations between the intake of total and individual classes and subclasses of (poly)phenols and the risk of lymphoma, including main frequent subtypes in the EPIC cohort using multivariable-adjusted Cox proportional hazards models. During a mean 14-year follow-up (time frame: from 1990-1994 to 2008-2013), 2394 incident lymphoma cases were diagnosed from a total of 367,463 individuals. No significant associations were observed between total intakes of (poly)phenols, flavonoids, and phenolic acids and overall lymphoma risk. Total (poly)phenols, phenolic acid and hydroxycinnamic acid intakes were positively associated with Hodgkin lymphoma (HL) risk [HRlog2 = 2.56 (95% confidence interval: 1.27-5.16); 1.81 (1.14-2.87); and 1.48 (1.03-2.12), respectively]. Conversely, isoflavone intakes was inversely associated with risk of overall lymphoma [HRlog2 = 0.96 (0.93-0.99)], and non-Hodgkin lymphoma [HRlog2 = 0.95 (0.92-0.99)] and mature B-cell lymphoma [HRlog2 = 0.96 (0.92-0.99)], and flavone intakes with risk of multiple myeloma/plasma cell neoplasm [HRlog2 = 0.75 (0.60-0.95)]. Our findings suggest that isoflavone intakes may reduce the risk of overall lymphoma and specific lymphoma subtypes, while phenolic acids, particularly hydroxycinnamic acids might increase the risk of HL.

Complement factors regulate tumour immunity in the tumour microenvironment (TME). We investigated the functions of complement 5a (C5a) and its receptors, C5aR1 and C5aR2, in forming the C5a-C5aR1 and C5a-C5aR2 signaling axes in the immune TME of pancreatic ductal adenocarcinoma (PDAC). C5a, C5aR1 and C5aR2 were assessed in cancer cell cytoplasmic (c-) and stromal (s-) expressions in resected PDAC tissues. In vitro assays were conducted to examine endogenous C5aR1 functions in PDAC cells, and orthotopic transplantation was performed in a preclinical study. In immunohistochemistry, High C5a-C5aR1 c-axis was correlated with poor prognosis and High C5a-C5aR1 s-axis was associated with a decrease in CD8+ T cells and an increase in CD11b+ MDSCs. C5aR1 knockdown and CCX168, the specific C5aR1 inhibitor, impaired proliferation and the activation of the PI3K/mTOR pathway, and enhanced gemcitabine sensitivity by increasing apoptosis. The combination of CCX168 and gemcitabine/nab-paclitaxel demonstrated a significant reduction in tumour volume. The number of CD8+ T cells was significantly increased in CCX168-treated groups, whereas CCX168 treatment resulted in a decrease in MDSCs. The C5a-C5aR1 axis may exert a tumour-promoting effect on the TME in PDAC. CCX168 appears to modulate antitumour immunity, thereby warranting future complement-based immunomodulation therapies for PDAC.