Qinsong Sheng

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

Introduction: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study.Methods: Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively.Results: BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy.Discussion: Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through interactions with its receptor, Angiotensin-converting enzyme 2 (ACE2), causing severe acute respiratory syndrome and death in a considerable proportion of people. Patients infected with SARS-CoV-2 experience digestive symptoms. However, the precise protein expression atlas of ACE2 in the gastrointestinal tract remains unclear. In this study, we aimed to explore the ACE2 protein expression pattern and the underlying function of ACE2 in the gastrointestinal tract, including the colon, stomach, liver, and pancreas.Methods: We measured the protein expression of ACE2 in the gastrointestinal tract using immunohistochemical (IHC) staining with an ACE2-specific antibody of paraffin-embedded colon, stomach, liver, and pancreatic tissues. The correlation between the protein expression of ACE2 and the prognosis of patients with gastrointestinal cancers was analyzed by the log-rank (Mantel–Cox) test. The influence of ACE2 on colon, stomach, liver, and pancreatic tumor cell line proliferation was tested using a Cell Counting Kit 8 (CCK-8) assay.Results: ACE2 presented heterogeneous expression patterns in the gastrointestinal tract, and it showed a punctate distribution in hepatic cells. Compared to that in parallel adjacent non-tumor tissues, the protein expression of ACE2 was significantly increased in colon cancer, stomach cancer, and pancreatic cancer tissues but dramatically decreased in liver cancer tissues. However, the expression level of the ACE2 protein was not correlated with the survival of patients with gastrointestinal cancers. Consistently, ACE2 did not affect the proliferation of gastrointestinal cancer cells in vitro.Conclusion: The ACE2 protein is widely expressed in the gastrointestinal tract, and its expression is significantly altered in gastrointestinal tumor tissues. ACE2 is not an independent prognostic marker of gastrointestinal cancers.

Background: To understand the biological effect of gut microbiome on the progression of colorectal cancer (CRC), we sequenced the V3-V4 region of the 16S rRNA gene to illustrate the overall structure of microbiota in the CRC patients. Methods: In this study, a total of 66 CRC patients were dichotomized into different groups based on the following characteristics: paired tumor and adjacent normal tissues, distal and proximal CRC segments, MMR (-) and MMR (+), different TNM staging and clinic tumor staging. Results: By sequencing and comparing the microbial assemblages, our results indicated that 7 microbe genus (Fusobacterium, Faecalibacterium, Akkermansia, Ruminococcus2, Parabacteroides, Streptococcus, and f_Ruminococcaceae) were significantly different between tumor and adjacent normal tissues; and 5 microbe genus (Bacteroides, Fusobacterium, Faecalibacterium, Parabacteroides, and Ruminococcus2) were significantly different between distal and proximal CRC segments; only 2 microbe genus (f_Enterobacteriaceae and Granulicatella) were significantly different between MMR (-) and MMR (+); but there was no significant microbial difference were detected neither in the TNM staging nor in the clinic tumor staging. Conclusion: All these findings implied a better understanding of the alteration in the gut microbiome, which may offer new insight into diagnosing and therapying for CRC patients.

This study aimed to analyze and evaluate the feasibility of using carbon nanoparticles (CNs) to track lymph nodes (LNs) metastases in right colon tumors, especially for patients who underwent laparoscopic-assisted radical right hemicolectomy.