Few population-based studies on nasopharyngeal carcinoma (NPC) prognosis exist. Such real-world data with complete follow-up are needed to enable accurate estimation of survival probabilities and monitor progress in early detection and treatment. In a population-based study of 2529 patients with incident NPC in southern China diagnosed in 2010-2013, we developed a passive-active-passive follow-up strategy involving data linkage and direct contact to track patients' vital status, cause of death, and migration through December 31, 2018. We calculated 5-year survival probabilities by the Kaplan-Meier method, and estimated avoidable deaths comparing hypothetical scenarios and real-world observations. Early-stage (I-II) patients accounted for 11·5%, and 21·1% were treated in medical-university-affiliated or province-level hospitals. With a mean follow-up time of 5·5 years after diagnosis (98.3% complete), 5-year overall and NPC-specific survival probabilities were 70·1% and 74·5%. The 5-year overall survival probabilities for stage I, II, III, IVa, IVb, and IVc were 91·3%, 87·8%, 79·8%, 63·9%, 57·7%, and 34·4%, respectively. Survival of non-metastatic (I-IVb) population-based patients diagnosed in 2010-2013 was comparable to that of a hospital-based southern Chinese NPC cohort diagnosed in 1997-2007. Based on observed data, if all patients were diagnosed at stages I-II, then total avoidable deaths within 5 years after diagnosis would be 156 per 1000 patients. Real-world population-based NPC survival lags behind that of large hospital-based cohorts, but earlier diagnosis has the potential to substantially reduce mortality from NPC. Our results highlight the importance of improving the accessibility of health resources and promoting early detection of NPC.

Chemoresistance induced by cancer-associated fibroblasts (CAFs) is well recognized, yet its mechanisms remain unclear and no CAF-targeted therapies are available. Gastric cancer (GC) with extensive CAF infiltration correlates with poor prognosis, and emerging evidence highlights the GAS6/AXL axis in CAF-GC interactions. This study targets GAS6/AXL axis to overcome CAF-mediated chemoresistance and enhance chemotherapy efficacy. We investigated the effect of 9im, a selective AXL inhibitor, on CAF-induced chemoresistance in GC using transwell migration, western blotting, viability assays, flow cytometry, drug efflux assays and in vivo experiments. Transcriptome analysis identified chemoresistance-related genes, and luciferase assays assessed STAT3 binding to the ABCG1 promoter. RNA-ISH analyzed GAS6 + CAFs in GC samples, while public data evaluated the prognostic significance of ABCG1 and CAF markers. GAS6 expression was elevated in CAF. CAF-derived GAS6 promoted GC cell migration and chemoresistance via AXL activation, effects reversed by 9im. STAT3 bound to the ABCG1 promoter, enhancing expression, while STAT3 inhibition reduced ABCG1 levels. 9im restored chemosensitivity in GC models. Clinically, ABCG1 and CAF marker co-expression correlated with poor prognosis. CAF-derived GAS6 induces GC chemoresistance via the AXL/STAT3/ABCG1 pathway. 9im restores chemosensitivity by inhibiting AXL and ABCG1-mediated efflux. AXL inhibitors with chemotherapy may improve GC treatment.

In search of salivary biomarkers for Head Neck Squamous Cell Carcinoma (HNSCC), we found Cornulin to be the most downregulated(~10-fold) protein during our previous study, which identified 135 dysregulated proteins in the saliva of the patients. The currentstudy aimed to explore the role(s) of Cornulin in pathophysiology of HNSCC and its translational application. The sandwich ELISA and immunohistochemistry assessed the levels of Cornulin in the saliva and primary tumour tissues, respectively, in a cohort of 128 HNSCC patients. The effects of Cornulin modulation were evaluated in-vitro and in-vivo HNSCC models and associated mechanisms were explored by analysis of transcriptomic and proteomic signatures. Cornulin was significantly downregulated in saliva and tumour tissue, which was also associated with tumour differentiation and poor survival. Cell proliferation, migration, viability, and invasion were decreased in Cornulin overexpressed HNSCC cell lines, which was substantiated using in-vivo model, suggesting the anti-tumour role of Cornulin. We identified the probable mechanism throughcell cycle arrest in the G1 phase by upregulating p18 and reducing the free intracellular calcium. In conclusion, we report the multifaceted roles of Cornulin in HNSCC, as a potential prognostic biomarker with anti-tumour properties.

Lymph node (LN) metastasis is not only a prognostic indicator but also a driver of systemic immune suppression. However, the mechanisms of immune escape within LNs remain unclear. Our pan-cancer single-cell transcriptomic analysis integrated public and in-house datasets from 11 cancer types, comprising 859,744 cells across 132 samples. We subsequently applied unsupervised clustering and cell-type annotation to identify dominant immunosuppressive cell populations within metastatic lymph nodes. Focused transcriptomic and pathway enrichment analyses were used to characterize the molecular features of these populations. Mechanistic studies, including in vitro and in vivo functional assays, were conducted to elucidate the signaling pathways underlying their immunoregulatory activity. Our analysis revealed that LN metastases exhibit a profoundly immunosuppressive microenvironment compared to primary tumors, characterized by: (1) Significant enrichment of an IL-10-producing macrophage subpopulation (Galectin-9high) specifically in LNs; (2) Galectin-9-mediated activation of the BTK/STAT3 pathway, driving IL-10 secretion and creating an immune-tolerant niche; (3) STAT3 inhibition selectively depleted these macrophages and, combined with PD-1 blockade, reduced LN metastatic burden in vivo. Our study identifies a Galectin-9/BTK/STAT3 axis that drives macrophage-mediated immune suppression in LN metastases, offering a potential therapeutic strategy.

Angiogenesis is essential for colorectal cancer (CRC) progression. The role of serine/threonine kinase STK32C in this process remains unclear. STK32C expression was examined in CRC tissues and correlated with patient prognosis. In vitro assays evaluated endothelial proliferation, migration, and tube formation. Mechanisms were studied using immunoprecipitation, western blotting, and gene set enrichment analysis. In vivo, xenograft and Matrigel plug assays assessed tumor growth and angiogenesis. STK32C was markedly overexpressed in CRC and associated with poor outcomes. Overexpression promoted endothelial angiogenic behaviors, while knockout suppressed them. Mechanistically, STK32C directly phosphorylated STAT3 at Thr196, enhancing its binding to JAK2 and activating IL-6/JAK2/STAT3 signaling. In vivo, STK32C depletion reduced tumor growth, VEGF-A expression, and microvessel density, confirming its pro-angiogenic function. STK32C-mediated tumor angiogenesis relied on STAT3 Thr196 phosphorylation. STK32C acts as a pro-angiogenic driver in CRC by activating IL-6/JAK2/STAT3 signaling via STAT3 Thr196 phosphorylation. Its strong association with poor prognosis highlights STK32C as a potential biomarker and therapeutic target in anti-angiogenic therapy.

Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent type of primary liver cancer and lacks effective targeted therapy. Previously, we reported that B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1) drives the formation and development of ICC independent of Ink4A/Arf; however, the underlying mechanism remains unclear. Here, we report that hepatic leukaemia factor (HLF) acts as a tumour-suppressor gene in ICC and Bmi1 represses HLF to drive ICC initiation and progression. RNA sequencing was performed to find the downstream target of Bmi1 in ICC. Bioinformatic analysis and molecular biological techniques were used to examine the expression of Bmi1 and HLF in ICC. Effects of HLF silence or overexpression by lentivirus on cell proliferation or development were evaluated in human ICC cells, xenograft and primary ICC mouse models, respectively. The luciferase reporter assay was used to identify that Bmi1 regulates HLF. In ICC, HLF expression levels were inversely correlated with Bmi1. Overexpression of HLF inhibited the growth of ICC both in vitro and in vivo, whereas HLF knockout promoted ICC development in ICC mouse models. Importantly, HLF repression reversed the inhibitory effects of Bmi1 knockdown on cell survival, proliferation and colony formation. Luciferase reporter assay results indicated that Bmi1 represses HLF by directly binding to its promoter. These findings revealed the molecular mechanism through which Bmi1 promotes ICC formation and development and uncovered the role of HLF as a tumour suppressor in ICC.

Work-related determinants of return to work (RTW) after breast cancer (BC) have been poorly studied. We analysed data from 2095 patients with primary BC enrolled in the French multi-center prospective cohort CANTO between 2012 and 2018. We investigated the association between administrative, physical and psychosocial working conditions and RTW two years after diagnosis using Poisson regression with robust variance. All models were adjusted for age, education, having a partner or children, and clinical variables at diagnosis. Analyses stratified by education (up to/higher than high school) and by chemotherapy were conducted. Multiple imputations were performed. Having no weekly rest period of 48 consecutive hours (RR = 1.36 95% CI:1.09-1.81), strenuous work postures (RR = 1.48 95% CI:1.19-1.87) and shift work (RR = 1.40 95% CI:1.11-1.75) as well as low independence of decision making (RR = 1.33 95% CI:1.04-1.81) were associated with increased non-RTW. Not perceiving her own job as boring (RR = 0.61 95% CI:0.39-0.86) was associated with decreased non-RTW. Administrative working conditions did not impact RTW. Working conditions emerged as potential levers to help women RTW. Our results underline the need for more targeted rehabilitation programs and personalized interventions to effectively help women in their RTW journey after BC.

The optimal cut-off values of estrogen receptor (ER) and progesterone receptor (PgR) expression to define the positivity of ER and PgR have been under discussion for over a decade but remain controversial. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the St. Gallen International Expert Consensus recommended that breast cancers with ≥1% of ER or PgR expression should be considered hormone receptor (HR)-positive tumors but ER/PR expression of 1% to 10% should be reported as HR-low positive; however, among HER2-negative disease, data on the overall benefit of adjuvant endocrine therapies for patients with HR-low positive disease is limited, resulting in the revisiting of the definition of triple-negative breast cancer (TNBC). Defining HR-low positive disease by better understanding the biology is essential because of the recent advancement of neoadjuvant and adjuvant systemic therapy strategies, including immune checkpoint inhibitors (ICIs) for TNBC. Additionally, identifying who should be treated with adjuvant endocrine therapy, particularly those who have HR-low HER2-negative disease, which is currently treated as TNBC without adjuvant endocrine therapy, is a clinical unmet need. In clinical practice, treating physicians have tailored systemic treatment strategies using other clinical and pathological factors (i.e., age, grade, Ki-67, tumor size, lymph node involvement). There is no universal practice to treat patients with HR-low HER2-negative breast cancer. This review summarized the currently available data to define the clinically relevant optimal cut-off values of ER/PgR in neoadjuvant- and adjuvant-setting. We recommend considering creating a novel category of triple-negative like breast cancer (TN-like BC), which will require a therapeutic strategy different from conventional TNBC.

Tissue architecture of cancer deviates from that of normal tissue and is closely linked to various features of cancer, including invasion and tumor immunity. However, pan-cancer analyses of cancer tissue architecture (CTA) remain limited. We applied non-negative matrix factorization to the expression data of 593 CTA-related genes from 28 cancer types in the Cancer Genome Atlas Project dataset, identifying seven distinct CTA signatures. A fibrous collagen-related signature, which is related to fibroblasts and the extracellular matrix, was relatively ubiquitous and represents a universal feature of cancer. In contrast, those associated with cell-cell adhesion or cell-stroma adhesion exhibited high tissue specificity. These findings were validated using Pan-Cancer Analysis of Whole Genomes data, spatial transcriptomics, and in vivo and in vitro models. In renal cell carcinoma, we found a strong correlation between network-forming collagen and patient survival, supported by mouse experiments showing that perturbation of this collagen promotes tumor growth. Additionally, several gene mutations and copy number alterations were found to correlate with changes in CTA. Our results suggest that CTA can be understood as a combination of components that influence the pathological features of cancer.