Cellular Oncology最新文献

Background: Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality, but few noninvasive biomarkers exist to track disease progression or inform treatment strategies. Circulating tumor cells (CTCs) offer a minimally invasive source of tumor material, yet the prognostic significance of their genomic diversity remains unclear.

Methods: We conducted whole-exome sequencing of CTC pools from 29 mCRC patients to characterize their mutational landscape and assess associations with overall survival.

Results: Our analysis revealed substantial variation in mutational burden among patients, with all CTC pools harboring non-silent mutations in key CRC driver genes. Higher genomic diversity in CTC pools was significantly associated with reduced overall survival. Additionally, non-silent mutations in BCL9L emerged as a strong predictor of patient survival.

Conclusion: Genomic diversity and BCL9L mutational status in CTC pools emerged as strong predictors of survival in mCRC, underscoring the potential of CTC genomic profiling as a minimally invasive and clinically relevant prognostic tool in mCRC.

Purpose: Colorectal cancer (CRC) remains a major global health challenge, necessitating novel therapeutic approaches. β-carboline alkaloids, natural compounds with anticancer properties, have shown potential to inhibit cancer cell viability. Here, we synthesized β-carboline derivatives and explored their potential as CRC inhibitors.

Methods: The IC₅₀ values of β-carboline derivatives were determined by cell viability assay. The biological effects of the leading candidate were evaluated via cell cycle analysis, proliferation assay, colony formation, apoptosis assay, and reactive oxygen species detection. Mechanistic studies were performed using transcriptomic and proteomic analysis, validated by immunoblotting, pulldown assay, cycloheximide-chasing assay, and co-immunoprecipitation. An in vivo CRC xenograft model was used to assess the efficacy of the leading candidate.

Results: Z-7 was identified as the leading candidate due to its ability to induce apoptosis and cell cycle arrest in CRC cells. Transcriptomic and proteomic data revealed that Z-7 activated the p53 signaling pathway in p53 wild-type CRC by binding to MDM2 at the RING domain, and inhibiting the E3 ligase activity of MDM2, leading to the reduction of p53 ubiquitination. In vivo study showed Z-7 treatment elevated p53 expression and significantly suppressed tumor growth in xenograft models.

Conclusion: Z-7 is a promising candidate for CRC therapy, particularly in patients with functional p53 and elevated MDM2, warranting further clinical evaluation.

Background: Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments.

Methods: We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions.

Results: MET inhibitors selectively suppressed tumour growth in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC.

Conclusion: Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.

Purpose: Interferon gamma (IFNG) directly affects the antitumor immune response. ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) is also positively correlated with poor prognosis for colorectal cancer (CRC). we performed some works to exploreexplored the underlying mechanism to further understand immune escape in colorectal cancer (CRC).

Methods: First, we used clinical samples to confirm the relationship between ST6GAL1 and CRC. Afterward, we constructed overexpression/knockdown cell lines and performed bulk RNA sequencing, kinase phosphorylation chip, mass spectrometry, and in vitro and in vivo assays to explore the mechanism regulated by ST6GAL1. Finally, we verified the mechanism by performing immunoprecipitation and immunofluorescence (IF) staining.

Results: ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) expression was negatively correlated with the response to neoadjuvant chemotherapy in patients with CRC and negatively correlated with the sensitivity to IFNG in CRC cell lines. We confirmed that ST6GAL1 overexpression inhibited the infiltration of effector T cells, the levels of IFNG produced by CD8⁺ T cells and CD4⁺ T cells decreased, and the levels of granzyme B produced by effector cells decreased in animal models. The results of in vitro assays and phosphorylation chip detection revealed that ST6GAL1 inhibited IFNG receptor 1 (IFNGR1) phosphorylation, thus decreasing the activation of the JAK1/STAT1 signaling pathway. Through immunoprecipitation assays and mass spectrometry, we found that ST6GAL1 can sialylate BICD cargo adaptor 2 (BICD2), thereby affecting the interaction between BICD2 and IFNGR1 to ultimately inhibit the phosphorylation of IFNGR1 and promote immune escape.

Conclusions: Our results confirmed that ST6GAL1 decreases the sensitivity of tumor cells to IFNG. This study describes a novel mechanism by which ST6GAL1 promotes the immune escape and malignant progression of CRC.

Metastasis, the leading cause of cancer-related mortality, is a complex process involving tumor cell detachment from the primary site, survival and dissemination through the circulation, and colonization of distant organs. At each stage, tumor cells face adaptive pressures from successive biological and biomechanical challenges in the local microenvironment, which collectively shape their progression. Traditional in vitro models often fail to replicate these dynamics, while animal models are limited by species differences and restricted real-time monitoring. Microphysiological systems (MPS) have emerged as powerful tools to address these limitations, delivering physiologically relevant cues and precise experimental control to recapitulate step-specific metastatic contexts. This review outlines recent advances in MPS designs for modeling critical hallmarks of metastasis, beginning with matrix interactions, stromal cells, and mechanical forces from the tumor microenvironment that drive epithelial-mesenchymal transition and invasion. The discussion then transitions to MPS that reproduce vascular physiology during intravasation, circulation, and extravasation, and concludes with organ-specific environments for studying colonization and organotropic behavior in the final stages of metastasis. Additionally, common MPS configurations, categorized into horizontal and vertical compartmental arrangements, and strategies for integrating vascularization are explored. Together, these advances highlight the potential of MPS in elucidating metastatic mechanisms and advancing targeted therapies.

Objective: This study aimed to investigate the synergistic antitumor effects and immunoregulatory functions of the SUMOylation inhibitor TAK-981 in combination with the chemotherapeutic agent doxorubicin (DOX) in triple-negative breast cancer (TNBC), as well as to evaluate the safety of this combination strategy, particularly its mitigating effect on DOX-induced cardiotoxicity.

Methods: In vitro experiments were conducted to assess the effects of TAK-981 and DOX, both alone and in combination, on the type I interferon (IFN I) signaling pathway, cell proliferation, and apoptosis in TNBC cells. Mechanistic studies were performed to explore their impact on the IFN I/JAK1/STAT1 axis and the expression of the downstream NKG2D ligand NKG2DL (ULBP2). In vivo animal models were used to evaluate the antitumor efficacy of the combination therapy, its effect on natural killer (NK) cell activity, systemic toxicity, with a focus on its cardioprotective effects.

Results: TAK-981 activated IFN I signaling, and DOX further enhanced IFN I pathway activity. The two drugs demonstrated a synergistic effect, significantly inducing apoptosis and inhibiting proliferation in TNBC cells. Mechanistically, the TAK-981 and DOX combination targeted the IFN I/JAK1/STAT1 signaling axis, downregulating the expression of the NKG2D ligand (ULBP2) through suppression of the NF-κB pathway. In vivo experiments confirmed that the combination therapy effectively inhibited tumor growth, enhanced NK cell activity, and did not increase systemic toxicity. Notably, TAK-981 significantly alleviated DOX-induced cardiotoxicity, improved cardiac function, and reduced fibrosis.

Conclusion: The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment.