Senescence as a dictator of patient outcomes and therapeutic efficacies in human gastric cancer

Senescence is believed to be a pivotal player in the onset and progression of tumors as well as cancer therapy. However, the guiding roles of senescence in clinical outcomes and therapy selection for patients with cancer remain obscure, largely due to the absence of a feasible senescence signature. Here, by integrative analysis of single cell and bulk transcriptome data from multiple datasets of gastric cancer patients, we uncovered senescence as a veiled tumor feature characterized by senescence gene signature enriched, unexpectedly, in the noncancerous cells, and further identified two distinct senescence-associated subtypes based on the unsupervised clustering. Patients with the senescence subtype had higher tumor mutation loads and better prognosis as compared with the aggressive subtype. By the machine learning, we constructed a scoring system termed as senescore based on six signature genes: ADH1B, IL1A, SERPINE1, SPARC, EZH2, and TNFAIP2. Higher senescore demonstrated robustly predictive capability for longer overall and recurrence-free survival in 2290 gastric cancer samples, which was independently validated by the multiplex staining analysis of gastric cancer samples on the tissue microarray. Remarkably, the senescore signature served as a reliable predictor of chemotherapeutic and immunotherapeutic efficacies, with high-senescore patients benefited from immunotherapy, while low-senescore patients were responsive to chemotherapy. Collectively, we report senescence as a heretofore unrecognized hallmark of gastric cancer that impacts patient outcomes and therapeutic efficacy.

Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and tumor suppressor STK11 (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine KRAS/LKB1 co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of KRAS/LKB1 co-mutants. Here, we found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.

Identification of Morphologic Criteria Associated with Biochemical Recurrence in Intraductal Carcinoma of the Prostate

Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer strongly associated with an increased risk of biochemical recurrence (BCR). However, approximately 40% of men with IDC-P remain BCR-free five years after radical prostatectomy. In this retrospective multicenter study, we aimed to identify histologic criteria associated with BCR for IDC-P lesions. A total of 108 first-line radical prostatectomy specimens were reviewed. In our test cohort (n = 39), presence of larger duct size (>573 µm in diameter), cells with irregular nuclear contours (CINC) (≥5 CINC in two distinct high-power fields), high mitotic score (>1.81 mitoses/mm2), blood vessels, and comedonecrosis were associated with early BCR (<18 months) (p < 0.05). In our validation cohort (n = 69), the presence of CINC or blood vessels was independently associated with an increased risk of BCR (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.09–4.96, p = 0.029). When combining the criteria, the presence of any CINC, blood vessels, high mitotic score, or comedonecrosis showed a stronger association with BCR (HR 2.74, 95% CI 1.21–6.19, p = 0.015). Our results suggest that IDC-P can be classified as low versus high-risk of BCR. The defined morphologic criteria can be easily assessed and should be integrated for clinical application following validation in larger cohorts.

Imaging of Neuroendocrine Prostatic Carcinoma

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that typically has a high metastatic potential and poor prognosis in comparison to the adenocarcinoma subtype. Although it can arise de novo, NEPC much more commonly occurs as a mechanism of treatment resistance during therapy for conventional prostatic adenocarcinoma, the latter is also termed as castration-resistant prostate cancer (CRPC). The incidence of NEPC increases after hormonal therapy and they represent a challenge, both in the radiological and pathological diagnosis, as well as in the clinical management. This article provides a comprehensive imaging review of prostatic neuroendocrine tumors.

Advances in Single-Cell Sequencing Technology and its Applications in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is mainly treated with chemotherapy-based combination therapy. In recent years, the increasing development of single-cell sequencing (SCS) has become one of the most promising technologies in the field of biotechnology. The study of the heterogeneity of TNBC tumor cells using SCS will expand our current knowledge of metastasis, drug resistance mechanisms, mutations, and cloning in these cells; this will further guide clinical chemotherapy, targeted therapy, and immunotherapy. Relevant studies shown that SCS exactly plays an important role in clinical diagnosis and treatment. To highlight the role of SCS in the study of TNBC, we elaborate on the progress of research and the applications of SCS in TNBC.

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Basal-like breast cancer (BLBC) is the most aggressive subtype of breast tumors with poor prognosis and limited molecular-targeted therapy options. We show that BLBC cells have a high Cys demand and reprogrammed Cys metabolism. Patient-derived BLBC tumors from four different cohorts exhibited elevated expression of the transsulfuration enzyme cystathione β-synthetase (CBS). CBS silencing (shCBS) made BLBC cells less invasive, proliferate slower, more vulnerable to oxidative stress and cystine (CySSCy) deprivation, prone to ferroptosis, and less responsive to HIF1-α activation under hypoxia. shCBS xenograft tumors grew slower than controls and exhibited impaired angiogenesis and larger necrotic areas. Sulfur metabolite profiling suggested that realigned sulfide/persulfide-inducing functions of CBS are important in BLBC tumor progression. Supporting this, the exclusion of serine, a substrate of CBS for producing Cys but not for producing sulfide/persulfide, did not exacerbate CySSCy deprivation–induced ferroptosis in shCBS BLBC cells. Impaired Tyr phosphorylation was detected in shCBS cells and xenografts, likely due to persulfidation-inhibited phosphatase functions. Overexpression of cystathione γ-lyase (CSE), which can also contribute to cellular sulfide/persulfide production, compensated for the loss of CBS activities, and treatment of shCBS xenografts with a CSE inhibitor further blocked tumor growth. Glutathione and protein-Cys levels were not diminished in shCBS cells or xenografts, but levels of Cys persulfidation and the persulfide-catabolizing enzyme ETHE1 were suppressed. Finally, expression of enzymes of the oxidizing Cys catabolism pathway was diminished, but expression of the persulfide-producing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.

Rectal plasmablastic lymphoma in Ebstein Barr virus positive and human immunodeficiency virus negative subject after external radiation therapy for prostatic cancer

Plasmablastic lymphoma (PBL) represents a rare and aggressive subtype of diffuse large B cells lymphoma (DLBCL) most associated with the human immunodeficiency virus (HIV). Prognosis remains poor despite various treatment approaches. We describe an evolution at six months of HIV negative PBL and Ebstein Barr virus (EBV) positive PBL with chemotherapy. Role of radiotherapy is still unclear.

Presentation and Treatment of Aggressive, Triple-Negative Carcinosarcoma of the Breast

Breast carcinosarcoma is an aggressive subtype of cancer that accounts for less than a percent of all breast malignancies. Carcinosarcoma is difficult to diagnose and treat. In the following, we present a case of breast carcinosarcoma with the treatment method.

TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.

Inhibition of FOXO1-Mediated Autophagy Promotes Paclitaxel-Induced Apoptosis in MDA-MB-231 Cell Lines

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and often produces resistance to paclitaxel (PTX) therapy. Autophagy plays an important cytoprotective role in PTX-induced tumor cell death and targeting autophagy is promising to improve the efficacy of tumor chemotherapy in recent years. Here, we reported that PTX induced both apoptosis and autophagy of MDA-MB-231 cells, and inhibition of autophagy enable to promote apoptotic cell death. Furthermore, we found that FOXO1 enhanced PTX-induced autophagy by a transcriptional activation pattern in MDA-MB-231 cells, which was associated with its downstream target genes ATG5, VPS34, BECN1 and MAP1LC3B. The knockdown of FOXO1 attenuated the survival of MDA-MB-231 cells under the PTX treatment. These findings will be beneficial to improve the treatment efficacy of PTX and to develop the autophagic target therapy of TNBC.