Cancer Science最新文献

Comprehensive genomic profiling (CGP) is useful for optimizing targeted therapy and immunotherapy strategies for thoracic malignancies. This study aimed to evaluate the clinical utility and diagnostic complementarity of the in-house sequencing platform Rapid-Neo. We retrospectively analyzed 110 patients with thoracic malignancies who underwent Rapid-Neo testing. The baseline characteristics, sequencing results, concordance with companion diagnostics (CDx), and clinical outcomes were assessed. Of 110 patients, 100 (90.9%) had primary lung cancer. Rapid-Neo identified at least one genomic alteration in 99.1% of cases and well-established driver alterations in 66.0% of lung cancer cases. TMB-high and MSI-high statuses were observed in 9.0% and 2.0% of cases, respectively. Among the 90 cases with prior CDx, Rapid-Neo identified driver alterations in 10.0% of the cases, including EGFR, KRAS, MET, RET, and ERBB2, suggesting its potential to overcome the limitations of conventional CDx tests. High concordance (96.8%) was observed between the Rapid-Neo and CDx results, finally. In EGFR-mutant lung adenocarcinoma, high tumor mutation burden (TMB) was associated with a significantly shorter progression-free survival (PFS) after EGFR-TKI therapy (HR = 2.58, p = 0.018) and remained an independent prognostic factor in multivariate analysis. Furthermore, among patients receiving immune checkpoint inhibitors (ICIs), favorable genomic markers such as TMB-high or MSI-high were associated with prolonged PFS. Rapid-Neo demonstrated high sensitivity and concordance with CDx, while also identifying actionable driver alterations missed by the initial CDx. Moreover, the genomic markers identified by Rapid-Neo may provide predictive values for both targeted therapy and immunotherapy responses, supporting their integration into routine clinical decision-making.

Infiltration of resident memory T cells (TRMs) in the main tumor has been reported as a favorable prognostic factor. However, the role of TRMs in the lymph nodes (LNs) remains unclear. Thus, we examined the prognostic impact of TRMs infiltration within LNs of patients with gastric cancer (GC). Among 151 patients with metastasis to LN station No. 3, we classified them into two groups (CD103^hi and CD103^lo) based on the number of CD103⁺ T cells using immunohistochemical staining and analyzed the association between these groups and survival outcomes. We also examined the phenotype of CD8⁺ CD103⁺ T cells in the metastatic LNs using flow cytometry. Among patients with LN metastasis, metastasis to LN station No. 3 was significantly associated with a poor prognosis. There was a significant correlation between the number of CD8⁺ CD103⁺ T cells between the main lesion and the metastatic LNs. CD103^hi was associated with a favorable prognosis (5-year overall survival [OS], log-rank p = 0.001; 5-year recurrence free survival [RFS], log-rank p = 0.001). Among adjuvant chemotherapy cases, patients with CD103^hi exhibited significantly better OS and RFS than those with CD103^lo (OS, log-rank p < 0.001; RFS, log-rank p < 0.001). Flow cytometry revealed that PD-1 expression in CD8⁺ CD103⁺ T cells was higher in metastatic than in normal LNs. Among patients with CD103^hi, those with high PD-1 expression exhibited significantly better OS than those with low PD-1 expression. In conclusion, the infiltration of TRMs into LNs is a critical prognostic factor in GC.

Lung adenocarcinomas (LUADs) in never-smokers exhibit distinct molecular profiles from those of smokers, and their driver mutations are quite divergent. We aimed to evaluate the utility of RNA-seq for the molecular profiling of LUAD in Japanese never or light smokers. A hybridization capture-based RNA panel (TOP2-RNA) was used to confirm the validity of mutational and expression analyses of the panel in 122 Japanese LUAD cases. For the discovery cohort, 270 primary LUADs were molecularly profiled using TOP2-RNA. Whole transcriptome sequencing (WTS) was conducted for the samples without any oncogenic driver mutations. A risk score was developed using TOP2-RNA expression data to predict the prognosis of surgically resected LUAD. Driver oncogenes were identified in 180 cases (66.7%) of the discovery cohort. The frequency of MET ex14 skipping was high (12.6%) among cases without EGFR mutations. Actionable novel fusions of RDX-RASGRF1, PRKCI-RASGRF2, and OCLN-RASGRF2 were identified in three never-smoker cases by WTS. A functional assay identified that the expression of RASGRF fusions transformed the cells through phosphorylation of MEK, which was inhibited by cobimetinib treatment. High-risk patients defined by the risk score based on the four-gene signature had significantly worse RFS and OS for all stages and stage I patients in the discovery and validation cohorts. This study identified novel RASGRF1/2 fusions that might be targetable by MEK inhibitors. RNA-based molecular profiling could identify actionable mutations and assess the prognostic biomarkers for patient stratification to determine the optimal treatment based on the molecular profiling of individual LUAD cases.

The nucleolus, a prominent membrane-less nuclear compartment, is organized around ribosomal RNA (rRNA) gene (rDNA) clusters, known as nucleolar organizing regions (NORs), located on the short arms of acrocentric chromosomes. It serves as the primary site for ribosome biogenesis, an energy-intensive process crucial for cell growth and proliferation. This involves RNA polymerase I (Pol I)-mediated transcription of 47S precursor rRNA (pre-rRNA), pre-rRNA processing, and ribosomal subunit assembly, reflected in its tripartite structure maintained by liquid–liquid phase separation. Recent evidence indicates that only about 30% of nucleolar proteins are exclusively involved in ribosome production. The remaining proteome participates in diverse cellular functions, establishing the nucleolus as a multifunctional organelle. It functions as a critical stress sensor and signaling hub, responding to various intracellular insults such as nutrient starvation, DNA damage, and viral infection. Many chemotherapeutic agents also induce the response called nucleolar stress via disruption of the nucleolar structure or function, potentially leading to rDNA instability. Nucleolar stress frequently leads to dynamic transition of nucleolar proteins, inducing nucleolar reorganization. Of these, the stress induced by transcriptional changes leads to the unique nucleolar structures termed nucleolar caps and nucleolar necklaces. In this review, we summarize the recent findings about the molecular mechanism of nucleolar changes upon stresses and discuss the possible relationship between rDNA instability and cancer.

A low molecular compound originally developed as an anexelekto inhibitor, TP-0903, has been highlighted as a promising therapeutic agent for treating chronic lymphocytic leukemia, solid tumors, and drug-resistant AML. We investigated the in vitro effects of TP-0903 on a myelodysplastic syndrome (MDS)-derived cell line (MDS-L) and two myeloid leukemia cell lines. TP-0903 effectively inhibited cell proliferation and induced apoptosis in all three cell lines. In MDS-L cells, the PI3K/AKT and JAK/STAT3 pathways were inhibited, suggesting that this may be partly due to decreased direct interactions with hepatocyte growth factor receptor, commonly known as MET. Regarding its effect on the cell cycle, TP-0903 was found to impact the DNA damage response and cell cycle-related factors, particularly those centered around Aurora kinases. In MDS-L cells, inhibition of Aurora A phosphorylation led to decreased levels of BORA, which in turn suppressed polo-like kinase 1 activation. This suppression hindered mitosis initiation, resulting in cell cycle arrest at the G2/M phase. Additionally, chromosomal misregulation caused by Aurora A inhibition appeared to impair cell division and contribute to cell death. Gene expression profiling of MDS-L revealed changes in the ferroptosis-related genes, including HMOX1 and transferrin, along with elevated levels of reactive oxygen species and intracellular iron accumulation. These findings suggest the activation of an atypical ferroptosis pathway mediated through the TGF-β1/SMAD3 signaling pathway. Overall, these data indicate that TP-0903 may offer a novel therapeutic strategy for the treatment of refractory hematological malignancies.

Photodynamic therapy (PDT) is a noninvasive anticancer treatment that uses a photosensitizer and light irradiation. PDT generates reactive oxygen species (ROS), thereby inducing tumor cell death. Stimulation of the interferon gene (STING) activation is highlighted as an immunotherapeutic strategy for cancer treatment. However, the role of STING and ROS in cancer therapy remains unclear. We hypothesized that STING regulates ROS generation in PDT, and that STING loss alters ROS homeostasis and causes therapeutic resistance. We established STING knockout (KO) HCT116 cells and compared the therapeutic efficacy of talaporfin sodium (TS)-PDT in KO and parental cells. Cell death induction was analyzed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. ROS induction was analyzed using 2′,7′-dichlorofluorescin diacetate assay. STING-regulated gene activation was assessed by western blotting. Furthermore, the efficacy of STING agonist (2′-3′-cyclic GMP–AMP sodium and ADU-S100) and TS-PDT combination was assessed in a xenograft tumor model. STING KO suppressed cell death induced by TS-PDT (IC₅₀ 16.58 [±1.03] vs. 19.21 [±1.38] μmol/L). STING KO suppressed ROS generation of TS-PDT (mean fluorescence intensity, 4240 [±517.4] vs. 2234 [±551.9]). STING-dependent signaling was enhanced by TS-PDT, and these effects were eliminated by STING loss. The combination of STING agonist and TS-PDT exhibited significantly greater tumor growth inhibition than single therapy alone. STING is an important regulator of cellular ROS homeostasis and tumor cell susceptibility to ROS in PDT. Combining a STING agonist with PDT could enhance its therapeutic efficacy and may have potential for future clinical applications.

This letter argues that Japan's dependence on a single foreign company for classifying germline variants is delaying critical treatment for cancer patients. The author proposes establishing a national “Germline Expert Panel” to provide independent, timely oversight, and ensure patients receive appropriate care.

Desmoid fibromatosis (DF) is a refractory tumor with a high recurrence rate, resulting in severe organ's deformity, morbidity, and mortality. The cellular characteristics of DF remain elusive. Herein, we performed single-cell RNA sequencing (scRNA-seq) to reveal the cell landscape of DF. To uncover the exclusive characteristics of DF, we compared the transcriptional profile of DF with that of keloid fibroblast (KF) and normal fibroblast (NF) in the public data (GSE163973). When compared with KF and NF, mesenchymal fibroblasts were significantly expanded in DF. The mesenchymal fibroblasts were further divided into two subtypes according to the differentiation states, among which LAMP5⁺ SULF1⁺ fibroblasts may account for the hard property of DF by promoting tumor ossification. ADAM12 and CREB3L1 were identified as the specific marker and transcription factor for DF, respectively. Both the quiescent and proliferative COL11A1⁺ neural cells exerted dominant roles in the maintenance of the profibrotic microenvironment in DF through modulating extracellular matrix. This study revealed the heterogeneity of fibroblasts in DF for the first time. The novel gene markers and transcription factor identified in DF and the significance of neural cells in the tumor microenvironment may point to new directions for the targeted therapy of DF in the future.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and treatment-resistant subtype of castration-resistant prostate cancer (CRPC) that often emerges during progression under androgen-receptor (AR) pathway inhibition. While lineage plasticity in cancer cells has been recognized as a key mechanism of resistance, the role of the tumor microenvironment in driving this transition remains unclear. Among its cellular components, vascular endothelial cells can undergo endothelial-mesenchymal transition (EndoMT), a phenotypic shift associated with tumor progression and fibrosis. Here, we investigated whether EndoMT contributes to NEPC development. Human umbilical vein endothelial cells (HUVEC) were induced to undergo EndoMT using IL-1β and TGF-β2, and are hereafter referred to as EndoMTed HUVEC. EndoMTed HUVEC promoted neuroendocrine features and functional changes in LNCaP cells. Transcriptome analysis revealed marked upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in EndoMTed HUVEC. Neutralization of GM-CSF signaling using mavrilimumab, a monoclonal antibody targeting the GM-CSF receptor alpha (CSF2RA), and siRNA-mediated CSF2RA knockdown both suppressed the neuroendocrine phenotype and STAT3 signaling of LNCaP cells. Conversely, GM-CSF stimulation alone reproduced these changes. Enzalutamide-treated LNCaP cells secreted IL-1β and TGF-β2, which in turn triggered EndoMT, suggesting a reciprocal loop. These findings indicate that anti-androgen therapy may inadvertently promote NEPC through a paracrine loop involving tumor-derived cytokines and endothelial GM-CSF secretion, highlighting EndoMT as a microenvironmental driver of treatment resistance.

Programmed death ligand 1 (PDL1) suppresses T-cell immunity by engaging programmed cell death protein 1 (PD1), and its blockade can activate T-cell responses. Although PDL1 is a transmembrane protein, its intrinsic signaling role in regulating oncogenesis remains unclear. Our study reveals lung adenocarcinomas (ADCs) exhibit deficient PDL1 expression, which correlates with poor patient prognosis. TGF-β stimulation induced PDL1 expression, while silencing PDL1 in PDL1-high lung ADC cells enhanced colony formation, and PDL1 overexpression inhibited lung cancer cell growth. Cell cycle analysis indicated that PDL1 silencing increased S-phase entry in lung ADC cells. Furthermore, PDL1 expression reduced FAK, ERK, and AKT phosphorylation, increasing cell detachment from the substrate. Gene expression profiling identified TGFBI as a downstream molecule of PDL1. TGF-β induced TGFBI expression, and knockdown of TGFBI increased the growth of lung ADC cells. Given that TGF-β regulates CITED2 and p21^CIP1 to initiate cell growth arrest, we examined the PDL1-TGFBI axis's impact on these molecules. Knockdown of PDL1 or TGFBI induced CITED2 expression but decreased p21^CIP1 expression in lung ADC cells. Moreover, inhibiting FAK via pharmacologic or genetic approaches decreased CITED2 but increased p21^CIP1 expression in PDL1-silenced lung ADC cells. These findings suggest that intrinsic PDL1-TGFBI signaling inhibits FAK activation, affecting the CITED2 molecular switch, which induces p21^CIP1, ultimately leading to cell growth arrest. Our study provides insights into intrinsic PDL1 signaling in lung ADC oncogenesis and indicates that PDL1 expression could be a biomarker for lung ADC progression.