Cancer letters最新文献

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation. In CAFs and tumor cells, however, a lack of YAP1 phosphorylation results in its translocation to the nucleus, binding to TEAD transcription factors, and activation of mitogenic pathways. In this review we summarize the literature discussing the central role of YAP1 in CAF activation, the upstream cues that promote YAP1-mediated CAF activation and extracellular matrix remodeling, and how CAFs mediate tumor-stroma crosstalk to support progression, invasion and metastasis in various cancer models. We further highlight YAP1⁺CAFs functions in modulating an immunosuppressive tumor microenvironment and propose evaluation of several YAP1 targets regarding their role in regulating intra-tumoral immune landscapes. Finally, we propose that co-administration of YAP1- targeted therapies with immune checkpoint inhibitors can improve therapeutic outcomes in patients with advanced tumors.

Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10⁻¹¹) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3β, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kβ inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kβ did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRβ, GSK3β, STAT3, and STAT6. RNA silencing of PDGFRβ in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRβ signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.

Immune checkpoints inhibitors (ICIs) as anti-PD-1/anti-PD-L1 have been approved as first-line treatment in patients with non-small cell lung cancer (NSCLC), but only 25 % of patients achieve durable response. We previously unveiled that estrogen receptor α transcriptionally up-regulates PD-L1 and aromatase inhibitors such as letrozole increase the efficacy of pembrolizumab. Here we investigated if letrozole may have additional immune-sensitizing mechanisms. We found that higher the level of PD-L1 in NSCLC, higher the activation of SREBP1c that transcriptionally increases fatty acid synthase and stearoyl-CoA desaturase enzymes, increasing the amount of polyunsaturated fatty acids (PUFAs). Letrozole further up-regulated SREBP1c-mediated transcription of lipogenic genes, and increased the amount of PUFAs, thereby leading to greater membrane fluidity and reduced binding between PD-L1 and PD-1. The same effects were observed upon supplementation with ω3-PUFA docosahexaenoic acid (DHA) that enhanced the efficacy of pembrolizumab in humanized NSCLC immune-xenografts. We suggest that PUFA enrichment in membrane phospholipids improves the efficacy of ICIs. We propose to repurpose letrozole or DHA as new immune-sensitizing agents in NSCLC.

Nerve invasion (NI) is a characteristic feature of pancreatic cancer. Traditional dichotomous statements on the presence of NI are unreasonable because almost all cases exhibit NI when sufficient pathological sections are examined. The critical implications of NI in pancreatic cancer highlight the need for a more effective criterion. This study included 511 patients, who were categorized into a training group and a testing group at a ratio of 7:3. According to the traditional definition, NI was observed in 91.2 % of patients using five pathological slides in our study. The prevalence of NI increased as more pathological slides were used. The criterion of ‘two points of intraneural (endoneural) invasion in the case of four pathological slides’ has the highest receiver operating characteristic (ROC) score. Based on this new criterion, NI was proved to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) and was also correlated with tumor recurrence (P = 0.004). Interestingly, gemcitabine-based chemotherapy regimen is an independent favorable factor for patients with high NI. In the high NI group, patients who received a gemcitabine-based regimen exhibited a better prognosis than those who did not receive the gemcitabine-based regimen for OS (P = 0.000) and DFS (P = 0.001). In conclusion, this study establishes assessment criteria to evaluate the severity of NI in order to predict patient outcomes.

Recently approved RET tyrosine kinase inhibitors (TKIs) have shown promising therapeutic effects against RET-rearranged non-small cell lung cancer (NSCLC) or RET-mutated thyroid cancer. However, resistance develops, limiting long-term efficacy. Although many RET-TKI resistance mechanisms, such as secondary mutations in RET or activation of bypass pathways, are known, some primary or acquired resistance mechanisms are unclear. Here, human genome-wide CRISPR/Cas9 screening was performed to identify genes related to drug-tolerant persister cells. Patient-derived cells with RET-fusion were introduced genome-wide sgRNA library and treated with RET-TKI for 9 days, resulting in the discovery of several candidate genes. Knockout of MED12 or MIG6 significantly increased residual drug-tolerant persister cells under RET-TKI treatment. MIG6 loss induced significant EGFR activation even with low concentrations of EGFR ligands and led to resistance to RET-TKIs. EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. By contrast, a KIF5B-RET positive cells established from a RET-rearranged NSCLC patient, showed significant resistance to RET-TKIs and high dependence on EGFR bypass signaling. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC.

Metastasis continues to negatively impact individuals diagnosed with colorectal cancer (CRC). Research has revealed the important role of long noncoding RNAs (lncRNAs) in CRC metastasis, but the underlying mechanisms remain unclear. Here, we revealed that the lncRNA small nucleolar RNA host gene 1 (SNHG1) is expressed at higher levels in metastatic CRC tissues than in primary CRC tissues, and that high lncRNA SNHG1 expression indicates poor patient outcomes. We found that lncRNA SNHG1 promotes the migration and invasion of tumor cells both in vivo and in vitro. Moreover, lncRNA SNHG1 increases serpin family A member 3 (SERPINA3) mRNA stability by interacting with the heterogeneous nuclear ribonucleoprotein D (HNRNPD) protein, and subsequently upregulates SERPINA3 expression. Moreover, HNRNPD and SERPINA3 reversed the effects of lncRNA SNHG1 knockdown on CRC cell metastasis. In conclusion, we report that the lncRNA SNHG1 recruits HNRNPD, in turn upregulating SERPINA3 expression and ultimately facilitating CRC cell migration and invasion. Targeting the lncRNA SNHG1/HNRNPD/SERPINA3 signaling pathway might be a therapeutic option for preventing CRC metastasis.

Cell-free DNA (cfDNA) analysis has shown potential in detecting early-stage lung cancer based on non-genetic features. To distinguish patients with lung cancer from healthy individuals, peripheral blood were collected from 926 lung cancer patients and 611 healthy individuals followed by cfDNA extraction. Low-pass whole genome sequencing and targeted methylation sequencing were conducted and various features of cfDNA were evaluated. With our customized algorithm using the most optimal features, the ensemble stacked model was constructed, called ESim-seq (Early Screening tech with Integrated Model). In the independent validation cohort, the ESim-seq model achieved an area under the curve (AUC) of 0.948 (95 % CI: 0.915–0.981), with a sensitivity of 79.3 % (95 % CI: 71.5–87.0 %) across all stages at a specificity of 96.0 % (95 % CI: 90.6–100.0 %). Specifically, the sensitivity of the ESim-seq model was 76.5 % (95 % CI: 67.3–85.8 %) in stage I patients, 100 % (95 % CI: 100.0–100.0 %) in stage II patients, 100 % (95 % CI: 100.0–100.0 %) in stage III patients and 87.5 % (95 % CI: 64.6%–100.0 %) in stage IV patients in the independent validation cohort. Besides, we constructed LCSC model (Lung Cancer Subtype multiple Classification), which was able to accurately distinguish patients with small cell lung cancer from those with non-small cell lung cancer, achieving an AUC of 0.961 (95 % CI: 0.949–0.957). The present study has established a framework for assessing cfDNA features and demonstrated the benefits of integrating multiple features for early detection of lung cancer.

Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway.