bims-metorg 2025-12-14 papers

Issue of 2025–12–14
six papers selected by
Bruna Martins Garcia, CABIMER

Expert Rev Anticancer Ther. 2025 Dec 10. 1-9

Genomic divergence between matched primary and metastatic tumors across cancer types: a pan-cancer analysis of 5,692 samples.

Yakup Ergun.

BACKGROUND: Metastasis is the leading cause of cancer-related death and involves biological processes such as genomic instability and immune evasion. Although metastatic tumors generally retain major alterations present in primary tumors, the extent of additional genomic divergence across cancer types remains insufficiently characterized.
RESEARCH DESIGN AND METHODS: A pan-cancer analysis was performed using targeted sequencing data from 2846 patients with matched primary and metastatic tumors (5692 samples) from the AACR Project GENIE-v18.0 cohort. Comparisons between primary and metastatic samples included mutation count, fraction of genome altered (FGA), gene-level mutation frequencies, copy number alterations (CNA), and structural variants (SV).
RESULTS: Metastatic tumors showed modest but statistically significant increases in mutation count (median 6 vs. 5) and FGA (0.186 vs. 0.140), with the largest differences observed in lung, breast, colorectal, pancreatic, and prostate cancers. Eleven genes, including KDM5A, CDKN2A, MYC, ESR1, and AR, were more frequently altered in metastases. Differences in CNA and SV patterns were also observed, particularly in genes involved in cell cycle control and DNA repair.
CONCLUSIONS: Compared with primary tumors, metastatic tumors demonstrated small but consistent genomic differences. These findings varied across cancer types and may reflect changes associated with the evolutionary transition from primary to metastatic disease.

Keywords: Genomic instability; metastasis; mutation count; pan-cancer analysis; primary tumor; somatic mutation

DOI: https://doi.org/10.1080/14737140.2025.2601769

Nanomedicine. 2025 Dec 08. pii: S1549-9634(25)00091-7. [Epub ahead of print] 102890

Multi-Organ-on-Chip approach to exploring breast cancer liver metastases concerning the endothelial barrier and the influence of immune cells.

Joanna Konopka, Joanna Roszczyk, Elżbieta Jastrzębska, Agnieszka Żuchowska.

Cancer metastasis is the spread of cancerous cells through the circulatory system to distant organs. Existing in vitro models remain insufficient to faithfully reproduce the metastatic process. Multi-Organ-on-Chip (multi-OoC) platforms allow the integration of complex tissue models. Here, we propose a microplatform that recapitulates breast cancer (BC) migration to the liver, considering an endothelial barrier (EB) and immune cell interactions. Tissue micromodels were created using agarose multi-wells, loaded into the microplatform, and separated by different types of barriers: (i) collagen type I, (ii) cell culture medium, (iii) immune (Jurkat) cells, (iv) a microvessel, and (v) a microvessel perfused with Jurkat cells. Spatial arrangement of cells, their morphology, and viability were imaged using fluorescence microscopy over 10-day experiments. Quantitative data such as Feret Diameter, relative Raw Integrated Density (ID) and migration distance of tumor cells (GFP-MDA-MB-231) were evaluated. The concentrations of metastatic agents (interleukin-6 (IL-6), and interleukin-11 (IL-11)) were determined using ELISA. The potential of a microplatform in drug screening was preliminarily assessed with the use of Doxorubicin (Dox) over a 7-day experiment. Changes in Feret diameter and ID indicated a gradual disintegration of the BC micromodel. BC cells migrated toward the liver micromodel through a barrier formed in the central microchannel. An EB was impenetrable for GFP-MDA-MB-231, whereas Jurkat cells promoted the migration of BC cells. Dox induced transient inflammation and suppressed IL-11-dependent pro-metastatic signaling, consistent with its dual cytotoxic and immunomodulatory roles.

Keywords: Breast cancer; Doxorubicin; Endothelial barrier; Immune cells; Interleukins; Liver metastasis; Multi-organ-on-Chip

DOI: https://doi.org/10.1016/j.nano.2025.102890

Phytomedicine. 2025 Dec 07. pii: S0944-7113(25)01315-7. [Epub ahead of print]150 157680

Jianpi Jiedu formula modulates glutamine metabolism to inhibit colorectal cancer liver metastasis.

Yicun Han, Yiran Ouyang, Yunzhou Pu, Peishan Zhou, Liu Yang, Wanli Deng, Qing Song, Qing Ji.

BACKGROUND: Liver metastasis is a primary cause of mortality in colorectal cancer (CRC) patients and significantly impacts patient prognosis. Jianpi Jiedu formula (JPJDF), a traditional Chinese medicine composed of six herbal ingredients, demonstrates clinically proven anti-metastatic efficacy against CRC.
PURPOSE: This study investigates the therapeutic potential of JPJDF for CRC metastasis and elucidates its regulatory mechanisms targeting glutamine metabolism.
METHODS: Mass spectrometry identified blood-absorbed anticancer bioactive compounds in JPJDF and evaluated their pharmacokinetics. Energy metabolomics compared metabolic profiles between healthy liver and CRC liver metastatic tissues. A murine CRC liver metastasis model was established. Anti-metastatic effects were assessed via small-animal in vivo imaging and tumor volumetry. Glutamine/glutamate assays, immunofluorescence, flow cytometry, and molecular biology techniques explored JPJDF's mechanistic role in glutamine metabolism regulation and immune modulation across in vivo and in vitro systems.
RESULTS: Following administration, bioactive compounds derived from JPJDF with anticancer activity were detected in the systemic circulation. JPJDF dose-dependently suppressed primary tumor growth and distant metastasis. Liver metastasis exhibited pronounced glutamine metabolic reprogramming. JPJDF inhibited metastasis by modulating glutamine metabolism in metastatic niches through the YTHDF1/GID8 axis. Mechanistically, this axis mediates SLC1A3/GLS pathway suppression, reducing glutamine utilization by CRC cells. Furthermore, comprehensive immunophenotyping of metastatic liver lesions revealed that JPJDF effectively reversed the immunosuppressive TME, characterized by reduced macrophage infiltration and increased abundance of T lymphocytes and mature dendritic cells.
CONCLUSION: JPJDF suppresses CRC metastasis by targeting glutamine metabolism via the YTHDF1/GID8 axis and by remodeling the immunosuppressive tumor microenvironment, highlighting its potential as an adjunct therapeutic strategy for metastatic CRC.

Keywords: Colorectal cancer; Glutamine metabolism; Jianpi Jiedu formula; Liver metastasis; SLC1A3/GLS; YTHDF1/GID8

DOI: https://doi.org/10.1016/j.phymed.2025.157680

Am J Psychother. 2025 Dec 08. appipsychotherapy20250015

Evidence-Based Psychotherapy Training in Residency and Graduate Programs: A Multidisciplinary Survey.

Luis E Flores, Danielle M Novick, Kelsey A Bonfils, Sarah E Bledsoe, Meredith Spada, Talia van der Vyver, Myrna M Weissman, Laura Mufson, John C Markowitz.

OBJECTIVE: Training in evidence-based psychotherapies (EBPs) in clinical programs is crucial for increasing their use in practice. Twenty years ago, the National Psychotherapy Training Survey-I (NPTS-I) examined whether U.S. training programs required didactic training and clinical supervision in EBPs. Almost all psychiatry (96%) programs, but only 56% of clinical psychology Ph.D., 33% of clinical psychology Psy.D., and 38% of social work (i.e., M.S.W.) programs, required EBP training. After years of dissemination efforts, the authors reexamined EBP training levels across those disciplines as well as counseling psychology and psychiatric-mental health nurse practitioner (PMHNP) programs by conducting the NPTS-II.
METHODS: Half of accredited training programs in each discipline were randomly selected for an online survey of training requirements and electives, whether all trainees receive EBP training, and associated barriers and facilitators. Of 574 invited programs, 253 (44%) program directors completed responses: 48 psychiatry (37%), 44 clinical psychology Ph.D. (53%), 14 clinical psychology Psy.D. (36%), 34 counseling psychology (58%), 38 PMHNP (35%), and 75 M.S.W. (49%) programs.
RESULTS: At least 75% of programs across disciplines offered didactic and clinical supervision EBP training. Required training rates were higher in psychiatry (90%) and clinical psychology Ph.D. (81%) programs than in clinical psychology Psy.D. (59%), PMHNP (48%), counseling psychology (28%), and M.S.W. (27%) programs. A similar pattern emerged in estimations of all trainees receiving EBP training.
CONCLUSIONS: EBP training requirements held steady in psychiatry and increased in clinical psychology programs. Low EBP training rates persist in other disciplines, possibly contributing to the continuing gap between EBP research efficacy evidence and practice.

Keywords: Barriers; Dissemination; Evidence-Based Psychotherapy; Facilitators; Psychotherapy Training

DOI: https://doi.org/10.1176/appi.psychotherapy.20250015

Transl Lung Cancer Res. 2025 Nov 30. 14(11): 4868-4895

Establishment and characterization of an orthotopic implanted lung cancer model to mimic human tumor structure, microenvironment, and metastatic spread.

Beñat Picabea, Daniel Orive, Covadonga Rodríguez, Miren Mailharin, María Sangüesa, Maeva Houry, Andrea Arricibita, Mirari Echepare, Ane Álava, Cristina Viu-Idocin, Alfonso Calvo, Joaquín Fernández-Irigoyen, Enrique Santamaría, Mikel Ariz, Luis M Montuenga, Karmele Valencia.

Background: Subcutaneous (SC) lung tumor models are widely used in preclinical studies due to their technical simplicity but fail to recapitulate the complex microenvironment, immune landscape, and metastatic behavior of human lung cancers. These limitations hinder the translational value of such models, particularly in evaluating immunotherapies and metastasis-related mechanisms. There is a critical need for more physiologically relevant in vivo models that better reflect clinical tumor characteristics and disease progression. To address these limitations, we sought to develop a reproducible orthotopic lung cancer (LuO) model that enables detailed study of tumor progression, immune infiltration, and metastatic dynamics.
Methods: We established and characterized a thoracotomy-based LuO model using a panel of human and murine lung cancer cell lines implanted into the pulmonary parenchyma of immunodeficient and syngeneic mice. Tumor progression was monitored longitudinally using bioluminescence imaging (BLI) and micro-computed tomography (CT). Comparative analyses with SC tumors were performed using immunohistochemistry, multiplexed immunofluorescence, transcriptomic and proteomic analyses. Circulating tumor cells (CTCs) and spontaneous metastases were isolated and functionally characterized.
Results: The orthotopic model reliably generated solitary intrapulmonary tumors that closely mimic human lung cancer in growth pattern, vascularization, and progression. Compared to SC tumors, orthotopic tumors exhibited significantly enhanced vascular density, reduced hypoxia and DNA damage, and increased proliferation. Immune profiling revealed enriched and spatially organized infiltrates of CD4+, CD8+ T cells, dendritic cells (DCs), and myeloid populations in orthotopic tumors, forming structures analogous to those found in patient tumors. Moreover, orthotopic tumors released CTCs capable of forming spontaneous and site-specific metastases to clinically relevant organs. Transcriptomic and proteomic profiling of metastasis-derived cell lines uncovered conserved pro-metastatic signatures and niche-specific adaptations.
Conclusions: This LuO model offers a reproducible, clinically relevant platform that captures important aspects of human lung cancer biology, including immune landscape, tumor microenvironment (TME), and metastatic progression. Its superior anatomical and immunological fidelity makes it a valuable preclinical tool for evaluating therapeutic strategies and dissecting molecular mechanisms of metastasis.

Keywords: Lung cancer; metastasis; mouse models; orthotopic; subcutaneous (SC)

DOI: https://doi.org/10.21037/tlcr-2025-871