bims-metorg 2025-11-23 papers

Issue of 2025–11–23
four papers selected by
Bruna Martins Garcia, CABIMER

MedComm (2020). 2025 Dec;6(12): e70477

Progression and Metastasis of Lung Cancer: Clinical Features, Molecular Mechanisms, and Clinical Managements.

Yunkui Zhang, Meixi Chen, Xumeng Fang, Yu Han, Yingke Li.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with metastasis leading to a poor prognosis. While advances in primary tumor management have improved survival, disease dissemination to distant organs, particularly the liver, bone, and brain, represents an unresolved therapeutic challenge. Metastasis is governed by complex interactions between tumor cells and the microenvironment, including immune evasion, angiogenesis, and organotropism. Current therapies often fail to address site-specific molecular vulnerabilities or overcome physiological barriers such as the blood-brain barrier (BBB). A systematic review integrating clinical and mechanistic insights is urgently needed to guide translational efforts. This review synthesizes evidence on lung cancer metastases to three critical sites: liver metastases, where immunosuppressive niches and delayed diagnosis limit outcomes, and we emphasize the role of immune checkpoint inhibitors and liquid biopsies; bone metastases, characterized by osteolytic/osteoblastic lesions, which require biomarker-driven therapies and multimodal pain management; and brain metastases, where BBB penetration and heterogeneity demand tailored approaches. By dissecting organ-specific mechanisms, including circulating tumor cells, premetastatic niche formation, and metabolic reprogramming, this work highlights actionable targets for precision medicine. This review advocates for patient stratification and combination therapies to improve survival, offering a roadmap for future research on metastatic lung cancer.

Keywords: bone metastasis; brain metastasis; liver metastasis; lung cancer

DOI: https://doi.org/10.1002/mco2.70477

Medicine (Baltimore). 2025 Oct 31. 104(44): e45570

Prognostic implications of organ-specific metastases in advanced gastric cancer: A retrospective observational analysis of the SEER database.

Guihua Liu, Junjun Gu, Jing Wang, Fang Li, Yi Shen, Zhimin Wang, Xianglong Tian.

Advanced gastric cancer (GC) remains a significant global health burden with poor prognosis. Understanding organ-specific metastatic patterns and their prognostic implications is critical for optimizing patient management. This study leverages the Surveillance Epidemiology and End Results database to comprehensively analyze metastatic patterns in GC and develop a robust prognostic model. We analyzed data from 10,842 GC patients diagnosed between 2010 and 2014, focusing on metastases to the liver, lungs, bones, and brain. Metastatic patterns, prognostic outcomes, and risk factors were evaluated using multivariable logistic and Cox regression analyses. A nomogram was developed to predict overall survival. Liver metastases were the most common (40.5%), followed by lung (13.5%), bone (11.0%), and brain (1.7%). Dual-organ metastasis most frequently involved the liver and lungs. Patients with isolated liver metastases had a relatively better prognosis (hazard ratio = 1.29, 95% confidence interval = 1.23-1.36, P < .0001), while those with isolated bone metastases had the poorest outcomes (hazard ratio = 1.99, 95% confidence interval = 1.63-1.96, P < .0001). Prognosis was uniformly poor for patients with metastases to 2 or more organs. Key risk factors included male sex, older age, and poorly differentiated tumors. A nomogram incorporating these factors demonstrated strong predictive accuracy. This study provides a comprehensive analysis of organ-specific metastatic patterns in GC, highlighting the prognostic significance of metastatic sites. The developed nomogram offers a practical tool for clinicians to predict survival outcomes and tailor treatment strategies for advanced GC patients.

Keywords: SEER; gastric cancer; metastases characteristics; nomogram; prognosis

DOI: https://doi.org/10.1097/MD.0000000000045570

Adv Sci (Weinh). 2025 Nov 16. e19858

Targeting the Hyperglycemic Pre-Metastatic Niche to Prevent Breast Cancer Bone Metastasis: Mechanisms and Therapeutic Strategies.

DuJiang Yang, Jiexiang Yang, GuoYou Wang.

The recent pioneering study by Ye et al. (Adv Sci. 2025;12(37):e0504924) provides compelling evidence that systemic hyperglycemia orchestrates a pre-metastatic niche (PMN) in bone, promoting breast cancer metastasis and identifying Receptor for Advanced Glycation End-products (RAGE) inhibition as a viable therapeutic strategy. While this work represents a significant conceptual advance by linking systemic metabolism to organotropic metastasis, the analysis identifies several substantive challenges that must be addressed to translate this finding into clinical practice. First, the authors clarify that the primary driver of enhanced bone metabolism is likely tumor-derived educative signals, with hyperglycemia acting as a secondary sensitizer rather than a sole instigator; this hierarchical causality requires further dissection. Second, the pleiotropic roles of RAGE in physiology and immunity raise concerns about the potential for on-target, adverse effects with long-term inhibition, necessitating the development of more targeted approaches. Finally, while the primary metabolic therapy proposed is GP-mediated glucose deprivation, the therapeutic efficacy demonstrated in a preventative model requires validation in scenarios of established micro-metastases, which mirror the clinical reality more closely. This critical appraisal underscores the need for a more nuanced understanding of the niche's biology and a rigorous evaluation of the proposed therapeutic paradigm's safety and timing.

Keywords: RAGE inhibition; breast cancer bone metastasis; glucose deprivation; hyperglycemia; pre‐metastatic niche; therapeutic targeting; tumor microenvironment

DOI: https://doi.org/10.1002/advs.202519858

Mod Pathol. 2025 Nov 19. pii: S0893-3952(25)00236-4. [Epub ahead of print] 100938

A Comprehensive Mutational and Histopathological Analysis of STK11-Mutant Non-Small Cell Lung Carcinomas.

Cristiana M Pineda, Zoe Guan, Hyunwoo Kwon, Deepa Rangachari, Daniel B Costa, Paul A VanderLaan.

Despite recent advances in the understanding of genomic and immunopathologic mechanisms of lung cancer, this disease remains the leading cause of cancer-related deaths in the United States. STK11 (LKB1) mutations are present in approximately 20% of non-small cell lung cancers (NSCLCs) and drive tumor progression through disruption of cellular metabolism, polarity, and stress responses ultimately leading to immune evasion and resistance to cancer therapy. Although these tumors are associated with poor prognoses, the clinicopathologic significance of different STK11 mutation subtypes and their associations with tumor histology, cellular behaviors, metastatic potential, and clinical outcomes remain incompletely understood. In this study, we retrospectively analyze a large cohort of STK11-mutant and STK11 wild-type NSCLCs using a combination of next generation sequencing, immunologic biomarkers, histopathologic characterization, and radiographic imaging. Overall, we demonstrate that STK11-mutant tumors display diverse molecular and morphologic features and are associated with high rates of aggressive histopathologic growth patterns, lymphovascular invasion, and spread through the airspaces (STAS). Among Stage 4 cases, STK11 mutations have notable differences in organotropism, with the STK11-loss cohort in particular demonstrating the highest rates of brain metastases at the time of initial diagnosis. Furthermore, among Stage 4 cases, while all STK11 mutation types result in decreased overall survival probability compared to the STK11 wild-type cohort, the effect appears most pronounced among the STK11-loss/KRAS-mutant group. These findings underscore the heterogeneity of STK11-mutant NSCLCs and highlight the opportunity for further investigation into specific STK11 mutation subtypes in guiding prognosis and therapeutic decision making for individuals with lung cancer.

Keywords: STK11; cancer genomics; co-mutational profile; next generation sequencing (NGS); non-small cell lung cancer (NSCLC)

DOI: https://doi.org/10.1016/j.modpat.2025.100938