bims-netuvo 2026-04-26 papers

BJUI Compass. 2026 Apr;7(4): e70196

Quantification of perineural invasion on prostate biopsy improves risk stratification in biopsy Grade Group 2-3 cancer.

Yuki Teramoto, Ying Wang, Hiroshi Miyamoto.

Objective: Perineural invasion (PNI) detected on prostate needle biopsy is a well-established indicator of adverse pathology, while the prognostic role of PNI quantification has recently been suggested. We herein aimed to determine whether PNI quantification could universally stratify risks by separately assessing subgroups of patients based on biopsy Grade Group (GG).
Methods: We quantified actual PNI foci in the entire systematic sextant biopsy specimens from 840 men, including 580 (69.0%) exhibiting no PNI and evaluated long-term oncologic outcomes following radical prostatectomy.
Results: PNI was detected in 1 (n = 177; 21.1%), 2 (n = 48; 5.7%) or 3-6 (n = 35; 4.2%) of 6 biopsy sites/parts, while 1 (n = 156; 18.6%), 2 (n = 53; 6.3%) or 3-10 (n = 51; 6.1%) PNI foci were present on each biopsy. In the entire cohort, we confirmed a significantly higher risk of biochemical recurrence in patients with PNI (vs. no PNI; P < 0.001), multi-site PNI (vs. single-site PNI; P < 0.001) or multifocal PNI (vs. unifocal PNI; P < 0.001). In subgroup analyses, significant differences in the risk of postoperative recurrence between the absence vs. presence of PNI were observed only in patients with GG3 or GG4 cancer. In contrast, the prognostic distinction between single-site vs. multi-site PNI or unifocal vs. multifocal PNI was evident in patients with GG2 or GG3 cancer, but not in those with GG1 or GG4-5 cancer. In multivariable analysis, multifocal PNI, but not multi-site PNI, was independently associated with worse recurrence-free survival in the GG2 (hazard ratio 5.866, P = 0.004) and GG3 (hazard ratio 2.716, P = 0.021) groups. Meanwhile, PNI on prostatectomy was confirmed in 98.1% of biopsy PNI-positive cases but was still detected in 72.2% of biopsy PNI-negative cases.
Conclusion: Quantification of actual PNI foci across all systematic biopsy sites may provide valuable prognostic information, particularly in patients with GG2-3 cancer. Notably, the mere presence of biopsy PNI may not universally predict poorer outcomes.

Keywords: needle biopsy; perineural invasion; prognosis; prostate cancer; radical prostatectomy

DOI: https://doi.org/10.1002/bco2.70196

Adv Sci (Weinh). 2026 Apr 22. e75426

Cancer-Associated Fibroblast-Derived Sphingosine-1-Phosphate Activates a MALL-SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer.

Wang Peng, Mengdie Cao, Hai Huang, Shuya Bai, Luyao Liu, Jingwen Liang, Haochen Cui, Qiaodan Zhou, Shiru Chen, Jiamei Jiang, Luoxia Liu, Zhou Luan, Wei Chen, Si Xiong, Ronghua Wang, Bin Cheng, Yuchong Zhao.

Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits perineural invasion (PNI), a clinicopathologic feature strongly associated with local recurrence and poor survival, yet lacking effective targeted interventions. By integrating patient cohorts with single-cell and bulk transcriptomics, multiplex immunofluorescence, and functional assays, this study defines a stromal-tumor signaling axis facilitating neural invasion. Cancer-associated fibroblasts (CAFs), particularly a myofibroblastic CAF-enriched population, upregulate sphingosine kinase 1 (SPHK1) and increase secretion of sphingosine-1-phosphate (S1P), which activates sphingosine-1-phosphate receptor 3 (S1PR3)/JNK/JUN signaling to transcriptionally induce MAL-like protein (MALL) in cancer cells. MALL binds to syndecan-4 (SDC4) and promotes its recycling to the plasma membrane, thereby increasing surface SDC4 abundance. This MALL-SDC4 program promotes RhoA/phosphorylated myosin light chain 2 (p-MLC2)-dependent amoeboid motility and sensitizes cancer cells to Schwann cell-derived pleiotrophin, strengthening directed neural invasion. Disruption of the axis through SPHK1 knockdown in CAFs, genetic perturbation of MALL or SDC4 in cancer cells, or adeno-associated virus-mediated SPHK1 or SDC4 knockdown in KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) mice significantly reduces PNI and tumor burden. These findings uncover a metabolite-driven MALL-SDC4 program connecting stromal metabolism to neural invasion, and identify promising therapeutic targets for PDAC.

Keywords: MAL‐like protein; Schwann cells; cancer‐associated fibroblasts; pancreatic ductal adenocarcinoma; perineural invasion; sphingosine‐1‐phosphate; tumor microenvironment

DOI: https://doi.org/10.1002/advs.75426

Gut. 2026 Apr 20. pii: gutjnl-2025-337595. [Epub ahead of print]

Norepinephrine promotes tumour cell aggressiveness and NK cell ferroptosis via ADRB2 in intrahepatic cholangiocarcinoma with perineural invasion.

Xian-Long Meng, Jia-Cheng Lu, Yi-Xiao Zhang, Pei Pu, Xiao-Jun Guo, Tao Zhu, Zhi-Qiang Hu, Lei Yu, Qi-Man Sun, Qiang Gao, Jian Zhou, Jia Fan, Yi Chen, Xiao-Yong Huang, Guo-Ming Shi.

BACKGROUND: Sympathetic signalling plays a critical role in the initiation and progression of various malignancies. However, its specific contribution to intrahepatic cholangiocarcinoma (iCCA) remains poorly understood.
OBJECTIVE: This study aimed to investigate the effects and underlying mechanisms of sympathetic signalling on tumour and immune cells, and to explore the potential efficacy of targeting sympathetic pathways in iCCA characterised by perineural invasion (PNI).
DESIGN: Single-cell RNA sequencing was employed to elucidate the impact of PNI on iCCA. In vivo and in vitro experiments were conducted to decipher the molecular mechanisms. Preclinical models were used to investigate the therapeutic potential of targeting sympathetic signalling.
RESULTS: Tyrosine hydroxylase-positive sympathetic nerve fibres were detected in PNI+ iCCA, accompanied by elevated norepinephrine (NE). We constructed an atlas of PNI+ iCCA at single-cell transcriptional level, characterised by MDK overexpression and reduced infiltration of CD56dimCD16+ natural killer (NK) cells. Mechanistically, NE was found to upregulate MDK expression via the ADRB2/PI3K-AKT/p65 axis, thereby promoting tumour progression of PNI+ iCCA. Furthermore, NE might induce NK cell ferroptosis by triggering an imbalance in glutamate/cysteine metabolism in PNI+ iCCA via ADRB2. Loss of sympathetic innervation in mice reduced NE concentrations and MDK expression, while increasing NK cell infiltration and inhibiting tumour growth. Preliminary results suggested that blockers of β-adrenergic receptors suppressed iCCA progression.
CONCLUSION: This study uncovers a novel neuro-immune-tumour axis in iCCA and provides a mechanistic rationale for targeting β-adrenergic signalling as a possible therapeutic strategy for PNI+ iCCA.

Keywords: CELL DEATH; CHOLANGIOCARCINOMA; IMMUNE RESPONSE; NEURAL-IMMUNE INTERACTIONS

DOI: https://doi.org/10.1136/gutjnl-2025-337595

Brain Behav Immun Health. 2026 Jul;54 101228

Perioperative psycho-behavioral stress promotes cancer metastasis beyond the impact of surgery: Neuroendocrine and tumor molecular mediating mechanisms.

Bar Bruno Shvalbo, Sharon Scarlat, Nahida Sakis, Estherina Trachtenberg, Elad Sandbank, Meshi Weil, Anabel Eckerling, Steven W Cole, Shamgar Ben-Eliyahu.

Clinically, the unique impact of perioperative distress on long-term cancer outcomes remains unclear and is thus overlooked medically. Operated cancer patients experience intertwined psychological and physiological stress, which are hard to disentangle. Therefore, herein we employed rodents to assess the specific impact of psycho-behavioral stress on cancer metastasis in the context of surgery and without it, and studied underlying neuroendocrine mechanisms and intratumoral transcriptional mediators. A tilt-light stress paradigm was employed along with surgery/tumor cell inoculation, using two mouse colorectal cancer models of liver metastases (MC38 C57BL/6, and CT26 BALB/c), and a rat mammary pulmonary metastases model (MADB106 F344). In the latter, we also assessed the efficacy of glucocorticoid, β-adrenergic, or COX-2 inhibitors/antagonists (mifepristone, propranolol, or etodolac) in preventing the effects of stress. A 48-h perioperative stress exposure, but not 24-h pre- or 24-h post-operative exposure, consistently increased the number of experimental metastases in all models, irrespective of the effects of surgery. Both mifepristone and propranolol, but not etodolac, prevented these effects. To better mimic the clinical setting, the 4T1 mammary cancer model of spontaneous metastases was used, along with six perioperative days of alternating stress. Perioperative stress increased metastasis, and a propranolol + etodolac regimen, as employed in recent clinical studies, abrogated pre-operative deleterious effects of stress on tumor epithelial-to-mesenchymal transition and other metastasis-related transcriptional activity. Overall, psycho-behavioral stress can uniquely contribute to metastatic progression through stress responses and malignant pro-metastatic transcriptional pathways. Thus, in cancer patients, managing perioperative distress may improve long-term cancer outcomes.

Keywords: Beta-blockers; Etodolac; Metastasis prevention; Mifepristone; Perioperative period; Propranolol; Psycho-behavioral stress; Stress models; Stress-inflammatory responses

DOI: https://doi.org/10.1016/j.bbih.2026.101228

Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00342-6. [Epub ahead of print]45(5): 117264

Q&A with Hua Zhong.

Hua Zhong.

Hua Zhong spoke with Cell Reports about their scientific journey and their work on the neural and immunological mechanisms driving lung cancer progression; in particular, they discussed their lab's recent Cell Reports paper on the role of the STMN2-β-alanine axis in regulating neuronal invasion in small cell lung cancer.

DOI: https://doi.org/10.1016/j.celrep.2026.117264