Juan Peng

Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing (WES), single-cell RNA-seq (scRNA-seq), PinpoRNA-HPV, bulk RNA-sequencing, and immunohistochemistry (IHC), we delineated its molecular architecture. Genomic profiling unveiled the dysregulation of 10 core oncogenic pathways and an exceptionally high tumor mutational burden (TMB), along with frequent alterations in DNA repair genes. ScRNA-seq analysis identified nine distinct malignant subclusters characterized by lineage plasticity (ASCL1/NEUROD1/UCHL1) alongside active HPV18 transcription. The tumor microenvironment exhibited a paradoxical immune landscape: dense infiltration of CD8+ T cells and CD163+ tumor-associated macrophages (TAMs) in the complete absence of tumoral PD1/PD-L1 expression. Cell–cell communication analysis revealed that malignant subclusters specifically overexpress CD47, engaging SIRB1 on TAMs and SIRPG on T cells. IHC validation confirmed a CD8+/CD163+/PD-L1-phenotype and demonstrated that transcriptional CD47 enrichment in malignant clones implicated the CD47-SIRB1 axis as the primary immune checkpoint. These findings indicated UCSCC as an HPV-driven, heterogeneous tumor that might employ CD47 as an alternative immune evasion pathway in the absence of PD-L1, providing a strong rationale for exploring CD47 blockade as a novel potentially therapeutic strategy.

Clinical efforts on precision medicine are driving the need for accurate diagnostic, new prognostic and novel drug predictive assays to inform patient selection and stratification for disease treatment. Accumulating evidence suggests that a combination of cancer pathology and artificial intelligence (AI) can meet this requirement. In the present review, the past, present and emerging integrations of AI into cancer pathology were comprehensively reviewed, which were divided into four main groups to highlight the roles of AI‑integrated cancer pathology in precision medicine. Furthermore, the unsolved problems and future challenges in AI‑integrated cancer pathology were also discussed. It was found that, although AI‑integrated cancer pathology could enable the amalgamation of complex morphological phenotypes with the multi‑omics datasets that drove precision medicine, synergies of cancer pathology with other medical tools could be more promising for the clinic when making an accurate and rapid decision in personalized treatments for patients. It was hypothesized by the authors that exploring the potential advantages of the multimodal integration of cancer pathology, imaging‑omics, protein‑omics and other‑omics, as well as clinical data to decide upon appropriate management and improve patient outcomes may be the most challenging issue of cancer precision medicine in the future.

Chemoresistance is the crux of clinical treatment failure of small‐cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin‐producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand‐independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand‐independent manner rather than a ligand‐dependent manner. Ligand‐independent EphA2 enhanced the expression of stemness‐associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial–mesenchymal transition (EMT) and reinforced self‐renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co‐immunoprecipitation (co‐IP) and GST‐pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti‐tumor effect with chemotherapy in preclinical models, including patient‐derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment.

Given that 3-phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in the malignant biological behaviors of a wide range of cancers, we review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and characterize the interaction networks of PDK1. Then, we establish the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More importantly, we sort the current preclinical or clinical trials of PDK1-targeted therapy in BC and find that, even though no selective PDK1 inhibitor is currently available for BC therapy, the combination trials of PDK1-targeted therapy and other agents have provided some benefit. Thus, there is increasing anticipation that PDK1-targeted therapy will have its space in future therapeutic approaches related to BC, and we hope the novel approaches of targeted therapy will be conducive to ameliorating the dismal prognosis of BC patients.

Given that 3-Phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in malignant biological behaviors of a wide-range of cancers, we further review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and extensively demonstrate the interacting networks of PDK1 via PI3K-dependent/ PI3K-independent pathway. Then we enlighten the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More important, we sort the current preclinical or clinical trials of PDK1 targeted therapy in BC and find that even though at present no selective PDK1 inhibitor is available for BC therapy, but the combination trials of PDK1 targeted therapy and other agents have demonstrated some benefit. Thus, there is increasing anticipations that PDK1 targeted therapy will have its space in future therapeutic concepts of BC, and we hope to feature PDK1 in BC to the clinic and bring the new promising to patients for targeted therapies.

This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal–epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.

Purpose: To evaluate the feasibility of implementing systematic patient symptom monitoring during treatment using a smartphone. Methods: Endometrial [n = 50], ovarian [n = 70] and breast [n = 193] cancer patients participated in text-based symptom reporting for up to 12 months. In order to promote equity, patients without a smartphone were provided with a device, with the phone charges paid by program funds. Each month, patients completed the Patient Health Questionnaire (PHQ-9), and 4 single items assessing fatigue, sleep quality, pain, and global quality of life during the past 7 days rated on a 0 (low) –10 (high) scale. Patients’ responses were captured using REDCap, with oncologists receiving monthly feedback. Lay navigators provided assistance to patients with non-medical needs. Results: Patients utilizing this voluntary program had an overall mean age of 60.5 (range 26–87), and 85% were non-Hispanic white. iPhones were provided to 42 patients, and navigation services were used by 69 patients. Average adherence with monthly surveys ranged between 75–77%, with breast patients having lower adherence after 5 months. The most commonly reported symptoms across cancer types were moderate levels (scores of 4–7) of fatigue and sleep disturbance. At 6 months, 71–77% of all patients believed the surveys were useful to them and their health care team. Conclusions: We established the feasibility of initiating and managing patients in a monthly text-based symptom-monitoring program. The provision of smartphones and patient navigation were unique and vital components of this program.

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial–mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Since the manifestation of PH varies from recurrent nephrolithiasis, nephrocalcinosis, and end-stage renal disease with age at onset of symptoms ranging from infancy to the sixth decade, the disease remains undiagnosed until after kidney transplantation in some cases. Herein, we report 3 cases of PH diagnosed after kidney transplantation failure, providing the comprehensive clinical course, the ultrasonic image of renal graft and pathologic image of the biopsy, highlighting the relevance of biopsy findings and the results of molecular genetic testing. We also focus on the treatment and the unfavorable outcome of the patients. Meanwhile, we review the literature and show the additional 10 reported cases of PH diagnosed after kidney transplantation. Additionally, we discuss the progressive molecular understanding of the mechanisms involved in PH and molecular therapy. Overall, the necessity of preoperative screening of PH in all patients even with a minor history of nephrolithiasis and the importance of proper treatment are the lessons we learn from the 3 cases, which prompt us to avoid tragedies.

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. It is well-known that estrogen plays an important role in the pathogenesis of endometrioid endometrial carcinoma (EEC), and induces the cancer suppressor gene PTEN deletion. However, how estrogen affects PTEN expression remains unknown. In the present study, we found in 40 EEC specimens, miR-200c level was higher in most cancer areas than that in the adjacent normal endometrium, while PTEN and PTENP1 were lower. Moreover, the expression of PTEN/PTENP1 and miR-200c also showed a converse relationship in EEC cell lines. In addition, we demonstrated that miR-200c bound directly to PTEN and PTENP1, and PTENP1 could reverse miR-200c inhibition function to PTEN using a dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays. Next, 17β-estradiol (E2) treatment could improve miR-200c and drop the PTEN level, which caused a consequential increase of the phospho-PI3K-AKT pathway genes. When we stably knocked down estrogen receptor α (ERα) expression in the EEC cell line, the effects of E2 on miR-200c and PTEN declined. In addition, it was demonstrated that E2 might modulate cell proliferation, migration and invasion relying on the expression of miR-200c. Taken together, it can be concluded that estrogen improves the miR-200c level by combining with ER, PTENP1 and PTEN could be inhibited by miR-200c, and then activate the PI3K-AKT pathway. This work provided a new mechanism of EEC development and a new potential therapeutic target.