Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

[Analysis of normal tissues adjacent to the tumour-specific expressed genes in breast cancer].

Normal tissues adjacent to the tumour (NAT) are widely used as controls in comparative studies to search for cancer-associated genes. However, the gene expression profiles between NAT and non-tumour-bearing tissues are different. The presence of NAT-specific expressed genes often hinders traditional transcriptional profiles studies. Further, studies on the differences in gene expression profiles between NAT and tumour-free tissues are infrequently performed. In this study, we sequenced and analysed the transcriptomes of tumour tissues (T), matched NAT and contralateral breast normal tissues (CBN) of 14 breast cancer patients, and identified 102 differentially expressed genes (DEGs) between CBN and NAT. Gene enrichment and protein-protein interaction (PPI) analyses revealed that these DEGs are significantly enriched in TNF (tumour necrosis factor) signalling and EMT (epithelial-mesenchymal transition) gene sets closely associated with oncogenesis. Comparative analyses of the transcriptomic profiles between NAT and CBN, NAT and T identified 23 NAT-specific highly-expressed genes, namely tumour-adjacent speci?cally activated (TASA) genes. These genes were significantly enriched in TNF signalling gene set, and 15 of which have not been previously reported. The results indicate that TASA genes are common in adjacent tissues and are related to the TNF signalling in the immune system. The tumour-adjacent tissues harbour tumour-like expressed genes that could contribute to tumour initiation but are often missed in NAT-T pair-wise studies.