Distinct Cancer Research Articles

Hydroquinone 5-O-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc.

Cancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the hydroquinone 5-O-cinnamoyl ester of renieramycin M (CIN-RM) was demonstrated to suppress lung cancer CSCs. CIN-RM was toxic to lung cancer cells with a half-maximal inhibitory concentration of around 15 µM. CIN-RM suppressed CSCs by inhibiting colony and tumor spheroid formation. In addition, the CSC population was isolated and treated and the CSCs were dispatched in response to CIN-RM within 24 h. CIN-RM was shown to abolish cellular c-Myc, a central survival and stem cell regulatory protein, with the depletion of CSC markers and stem cell transcription factors ALDH1A1, Oct4, Nanog, and Sox2. For up-stream regulation, we found that CIN-RM significantly inhibited Akt and consequently decreased the pluripotent transcription factors. CIN-RM also inhibited mTOR, while slightly decreasing p-GSK3β (Ser9) but rarely affected the protein kinase C (PKC) signal. Inhibiting Akt/mTOR induced ubiquitination of c-Myc and promoted degradation. The mechanism of how Akt regulates the stability of c-Myc was validated with the Akt inhibitor wortmannin. The computational analysis further confirmed the strong interaction between CIN-RM and the Akt protein with a binding affinity of −10.9 kcal/mol at its critical active site. Taken together, we utilized molecular experiments, the CSC phenotype, and molecular docking methods to reveal the novel suppressing the activity of this compound on CSCs to benefit CSC-targeted therapy for lung cancer treatment.

An Immune-Based Genomic Classifier (GC) Prognosticates for Survival in Endemic Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a distinct head and neck cancer that is associated with Epstein-Barr virus (EBV). Its histomorphology is characterized by epithelial carcinoma that is admixed with immune cells. This cellular pattern concurs with whole exome sequencing (WES) profiles of NPC that reveal several recurrent mutations involving NFKß and MHC-class genes, which are linked to poor outcomes. There is little information on the transcriptomic landscape of NPC. Here, we performed whole transcriptome sequencing (RNAseq) of a prospectively recruited cohort of NPC patients who were treated at a single institution.Patients with biopsy-proven NPC, staged using the UICC/AJCC 8th ed, were prospectively recruited under an institutional approved protocol. All formalin-fixed paraffin-embedded specimens were centrally reviewed. Specimens with tumor cellularity of > 70% were macrodissected and Ranse (Illumina Trusses, CA) was performed. All patients underwent radiotherapy (RT); concurrent (CRT) and/or induction (IC) or adjuvant chemotherapy (AC) was performed for patients with advanced NPC. Primary clinical endpoint was disease-free survival (DFS).Of 1,040 patients recruited, 145 patients had specimens that were successfully profiled by Ranse. Median age of this sub-cohort was 54.2 (IQR: 45.2-61.1) y; median follow-up was 4.8 (IQR: 3.3-8.1) y. Stage distribution was as such: 10 (6.9%) for Stage 1, 36 (24.8%) for Stage 2, 47 (32.4%) for Stage 3 and 41 (28.3%) for Stage 4A; 7 (4.8%) for Stage 4B; 4 (2.8%) were unclassified. 77 (53.1%) and 55 (37.9%) had EBV DNA titers of < 4,000 copies/ml and ≥4,000 copies/ml, respectively (13 [9.0%] missing). In terms of treatment received, 42 (29.0%) underwent RT alone; 50 (34.5%) and 41 (28.3%) received CRT and IC/AC+CRT; 12 (8.3%) had other treatment combinations. Unsupervised hierarchical clustering using expression of the top 1,000 most variable genes across the cohort revealed three distinct clusters that were characterized by differential expression of immune-related genes; incidentally, the cluster of patients with low immune score were enriched for recurrences, while the intermediate/high immune score groups had comparable prognoses. Subsequently, we performed gene-selection based on the low and intermediate/high immune score clusters and identified 511 genes that were significantly differentially expressed between them. We further clustered these genes to obtain a representative 5-gene GC that was prognostic for DFS (HR 3.28 [95% CI: 1.36-7.9]) on multivariable analyses, adjusted for T- and N-status and EBV DNA. Our GC was also prognostic for DFS in a validation dataset (N = 88, Zhang et al., 2017); HR 2.1 (95% CI: 0.73-6).Herein, we developed and validated an immune-based prognostic GC for NPC. Our findings underscore the importance of the immune landscape in EBV-positive NPC.

Understanding cancer caregiver burden over time: Dyadic assessments of family cohesion, conflict and communication

ObjectivePreviously we identified three distinct cancer communication concordance groups among cancer patient-caregiver dyads. This secondary analysis examined patient and caregiver reports of family functioning (cohesion and conflict) as associated with cancer communication concordance and assessed each as independent predictors of perceived caregiver burden among hematological cancer caregivers. MethodsA case series of hematological cancer patient-caregiver dyads (n = 171) were recruited from oncology clinics in Virginia and Pennsylvania and followed for 2 years. Using the previously identified communication groups this analysis prospectively examines patient and caregiver perceptions of family cohesion and conflict and the association with burden over time. ResultsCaregiver burden decreased over time. Caregiver, but not patient perceptions of family cohesion decreased over time; decreased cohesion and increased conflict was associated with greater cancer communication discordance. ConclusionsThis work lends further support to the use of cancer communication congruence typologies for identifying potentially vulnerable dyads. Discordant cancer communication and declining caregiver perceptions of family cohesion may represent opportunities to intervene using family focused supportive services. Practice implicationsOnly caregiver perceptions of family functioning were associated with burden therefore identifying and supporting those caregivers with worsening communication and family function is important.

Acute and long-term outcomes of ST-elevation myocardial infarction in cancer patients

Abstract Background Myocardial infarctions (MI) and cancer are each very serious morbidities. To evaluate their interaction in the “real world”, a retrospective analysis was performed in patients with ST-elevation MI (STEMI) and pre-existing cancer. Methods Anonymized data from patients admitted to hospital between 2010 and 2017 due to STEMI were analyzed from 24 months before and up to nine years after the index hospitalization by one of Germany's largest statutory Health Insurance Funds (Allgemeine Ortskrankenkasse - AOK). Qualitative data were tested via two-sided Chi-squared test and quantitative data were tested using a two- sided Wilcoxon test. The eight year overall survival (OS) rate was determined with a Kaplan Meier estimator. The endpoint OS was analysed using multivariable Cox-regression model. Results From 175,262 STEMI patients, 27,213 had cancer (15.5%). Most frequent were skin (24.9%), prostate (17.0%), colon (11.0%), breast (10.9%), urinary tract (10.6%), and lung cancer (5.2%). STEMI patients with malignancies were older, presented more often with coronary three-vessel-disease, classical risk factors, atrial arrhythmias, kidney disease, heart failure, cerebrovascular and peripheral artery disease (PAD) (each p&amp;lt;0.001). They showed more often previous MI, percutaneous coronary interventions (PCI), cardiac surgery, and stroke (all p&amp;lt;0.001). Acute PCIs were applied approximately 2–6 percent points less frequently compared to those without (w/o) cancer, with less drug-eluting and more often bare metal stents (all p&amp;lt;0.001). In-hospital adverse events occurred more frequently in cancer. Eight-year survival was 57.3% (95% CI 57.0% – 57.7%) w/o cancer, and ranged between 41.2% and 19.2% in distinct cancer types. Multivariable Cox regression for death during follow-up found e.g. lung cancer (HR 2.04, 95% CI 1.92–2.17), PAD stage 4–6 (HR 1.78, 95% CI 1.72–1.84) and previous stroke (HR 1.44, 95% CI 1.31–1.54) to have the strongest effect, while obesity (HR 0.95, 95% CI 0.93–0.97) was associated with lower mortality (all p&amp;lt;0.001). Conclusion In this large “real world” health insurance data from Germany, prognosis after STEMI was markedly reduced but differed widely between cancer types. No withholding of revascularization therapies in cancer patients could be observed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Federal Joint Committee, Innovation Committee (G-BA, Innovationsfonds, number 01VSF18051).

Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling

Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.

Impact of the Pd2Spm (Spermine) Complex on the Metabolism of Triple-Negative Breast Cancer Tumors of a Xenograft Mouse Model.

The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd2Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd2Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd2Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd2Spm complex in TNBC metabolism.

Papillary thyroid microcarcinoma: distinct form or cancer growth stage?

Background. Over the past decades an increase in the incidence of papillary thyroid microcarcinoma (PTMC) has been observed throughout the world owing to the improved diagnostics. There are many different opinions about the aggressiveness degree of this group of tumors, as well as about the tactics of managing patients with PTMC.Aim of the study is the identification of the prognostic factors responsible for the features of the clinical course, including the more aggressive one.Materials and methods. A study was carried out with a detailed analysis of a group of patients with papillary thyroid cancer ≤1 cm in size and the existing clinical data of regional and distant metastases. All patients underwent thyroidectomy with bilateral central cervical lymph node dissection. Factors such as gender, patient age, bilaterality, extrathyroid extension, the presence or absence of a capsule around the tumor node, the absence or presence of metastases in the central part were assessed. In 26.6% histological examination revealed metastatic lesions of the central group lymph nodes. Latent metastases were detected in 24.2% of women and 43% of men, in 36.7% of patients &lt;55 and in 14.3% of patients ≥ 55 years, in 29.5% with the absence of the node capsule and in 19.3% with encapsulated tumors, in 48.1% with multicentric growth and in 19.5% with a solitary neoplasm, in 21.7% with a tumor size ≤0.5 cm and in 27.9% with a node of 0.6–1 cm, in 24% with the absence of invasion of the thyroid capsule and in 31% with the presence of extrathyroid invasion, in 21% of patients with typical, in 26% with follicular and 43% with mixed papillary cancer. 95 patients received radioiodine therapy. No additional metastases were found in them.Results. When conducting univariate analysis, the main signs influencing the development of metastases in the central zone were age up to 55 years (p = 0.009, χ2 = 6.919) and multicentric neoplasm (p = 0.004, χ2 = 8.530); in multivariate analysis, similarly, age younger 55 years (p = 0.000, Exp B = 0.011, CI 95.0% 0.001–0.106) and multifocality (p = 0.027, Exp B = 2.686, CI 95.0% 1.119–6.448).Conclusion. PTMC is not a separate group or tumor morphotype, and the determination of treatment tactics for this group of patients should be based not only on the size of the tumor, but on the clinical and biological parameters of the tumor.

Cancer cell states and emergent properties of the dynamic tumor system.

Phenotypic heterogeneity within malignant cells of a tumor is emerging as a key property of tumorigenesis. Recent work using single-cell transcriptomics has led to the identification of distinct cancer cell states across a range of cancer types, but their functional relevance and the advantage that they provide to the tumor as a system remain elusive. We present here a definition of cancer cell states in terms of coherently and differentially expressed gene modules and review the origins, dynamics, and impact of states on the tumor system as a whole. The spectrum of cell states taken on by a malignant population may depend on cellular lineage, epigenetic history, genetic mutations, or environmental cues, which has implications for the relative stability or plasticity of individual states. Finally, evidence has emerged that malignant cells in different states may cooperate or compete within a tumor niche, thereby providing an evolutionary advantage to the tumor through increased immune evasion, drug resistance, or invasiveness. Uncovering the mechanisms that govern the origin and dynamics of cancer cell states in tumorigenesis may shed light on how heterogeneity contributes to tumor fitness and highlight vulnerabilities that can be exploited for therapy.

Cancer cell immune mimicry delineates onco-immunologic modulation

SummaryImmune transcripts are essential for depicting onco-immunologic interactions. However, whether cancer cells mimic immune transcripts to reprogram onco-immunologic interaction remains unclear. Here, single-cell transcriptomic analyses of 7,737 normal and 37,476 cancer cells reveal increased immune transcripts in cancer cells. Cells gradually acquire immune transcripts in malignant transformation. Notably, cancer cell-derived immune transcripts contribute to distinct prognoses of immune gene signatures. Optimized immune response signature (oIRS), obtained by excluding cancer-related immune genes from immune gene signatures, and offers a more reliable prognostic value. oIRS reveals that antigen presentation, NK cell killing and T cell signaling are associated with favorable prognosis. Patients with higher oIRS expression are associated with favorable responses to immunotherapy. Indeed, CD83+ cell infiltration, which indicates antigen presentation activity, predicts favorable prognosis in breast cancer. These findings unveil that immune mimicry is a distinct cancer hallmark, providing an example of cancer cell plasticity and a refined view of tumor microenvironment.

WNT as a Driver and Dependency in Cancer.

The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations can vary dramatically between different cancers, highlighting possible cancer-specific mechanisms for WNT-driven disease. In this review, we discuss how WNT pathway disruption contributes to tumorigenesis in different organs and how WNT affects the tumor cell and immune microenvironment. Finally, we describe recent and ongoing efforts to target oncogenic WNT signaling as a therapeutic strategy. SIGNIFICANCE: WNT signaling is a fundamental regulator of tissue homeostasis and oncogenic driver in many cancer types. In this review, we highlight recent advances in our understanding of WNT signaling in cancer, particularly the complexities of WNT activation in distinct cancer types, its role in immune evasion, and the challenge of targeting the WNT pathway as a therapeutic strategy.

Constitutive and variable 2’-O-methylation (Nm) in human ribosomal RNA

ABSTRACT Epitranscriptomic modifications of stable RNAs are dynamically regulated and specific profiles of 2ʹ-O-methylation in rRNA have been associated with distinct cancer types. However, these observations pointed out the existence of at least two distinct groups: a rather large group with constitutive rRNA Nm residues exhibiting a stable level of methylation and a more restricted set of variable modifications, giving rise to the concept of ‘specialized ribosomes’. These heterogeneous ribosomes can modulate their translational properties and be key regulatory players, depending on the physiological state of the cell. However, these conclusions were drawn from a limited set of explored human cell lines or tissues, mostly related to cancer cells of the same type. Here, we report a comprehensive analysis of human rRNA Nm modification variability observed for >15 human cell lines grown in different media and conditions. Our data demonstrate that human Nm sites can be classified into four groups, depending on their observed variability. About ⅓ of rRNA 2ʹ-O-methylations are almost invariably modified at the same level in all tested samples (stable modifications), the second group of relatively invariant modifications (another ½ of the total) showing a slightly higher variance (low variable group) and two variable groups, showing an important heterogeneity. Mapping of these four classes on the human ribosome 3D structure shows that stably modified positions are preferentially located in the important ribosome functional sites, while variable and highly variable residues are mostly distributed to the ribosome periphery. Possible relationships of such stable and variable modifications to the ribosome functions are discussed.

Dysregulated paired related homeobox\xa01 impacts on hepatocellular carcinoma phenotypes

BackgroundHepatocellular carcinoma (HCC) is a major cause of cancer-related death. Paired related homeobox 1 (PRRX1) is a transcription factor that regulates cell growth and differentiation, but its importance in HCC is unclear.MethodsWe examined the expression pattern of PRRX1 in nine microarray datasets of human HCC tumour samples (n > 1100) and analyzed its function in HCC cell lines. In addition, we performed gene set enrichment, Kaplan-Meier overall survival analysis, metabolomics and functional assays.ResultsPRRX1 is frequently upregulated in human HCC. Pathway enrichment analysis predicted a direct correlation between PRRX1 and focal adhesion and epithelial-mesenchymal transition. High expression of PRRX1 and low ZEB1 or high ZEB2 significantly predicted better overall survival in HCC patients. In contrast, metabolic processes correlated inversely and transcriptional analyses revealed that glycolysis, TCA cycle and amino acid metabolism were affected. These findings were confirmed by metabolomics analysis. At the phenotypic level, PRRX1 knockdown accelerated proliferation and clonogenicity in HCC cell lines.ConclusionsOur results suggest that PRRX1 controls metabolism, has a tumour suppressive role, and may function in cooperation with ZEB1/2. These findings have functional relevance in HCC, including in understanding transcriptional control of distinct cancer hallmarks.

MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.

Simple SummaryIn the last decade, metabolic reprogramming has emerged as a driving characteristic of cancer cells. The MYC oncogene, a transcription factor, has become of growing interest as a fundamental driver of differential cancer cell metabolism. Furthermore, the non-essential amino acid glutamine is deemed to be an important nutrient for cancer cells. In fact, glutamine can integrate into a wide variety of metabolic pathways, from energy metabolism to nucleotide synthesis. This review offers a comprehensive and specific overview of recent discoveries in the regulation of MYC oncogene activation on glutamine metabolism in cancer cells.Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Adjuvant Treatment Recommendations in Early-Stage Endometrial Cancer: What Changes With the Introduction of The Integrated Molecular-Based Risk Assessment.

Adjuvant therapy recommendations for endometrial cancer were historically based on the individual patient’s risk of disease recurrence using clinicopathologic factors such as age, stage, histologic subtype, tumor grade, and lymphovascular space invasion. Despite the excellent prognosis for early stages, considerable under- and overtreatment remains. Integrated genomic characterization by the Cancer Genome Atlas (TCGA) in 2013 defined four distinct endometrial cancer subgroups (POLE mutated, microsatellite instability, low copy number, and high copy number) with possible prognostic value. The validation of surrogate markers (p53, Mismatch repair deficiency, and POLE) to determine these subgroups and the addition of other molecular prognosticators (CTNNB1, L1CAM) resulted in a practical and clinically useful molecular classification tool. The incorporation of such molecular alterations into established clinicopathologic risk factors resulted in a refined, improved risk assessment. Thus, the ESGO/ESTRO/ESP consensus in 2020 defined for the first time different prognostic risk groups integrating molecular markers. Finally, the feasibility and clinical utility of molecular profiling for tailoring adjuvant therapy in the high-intermediate-risk group is currently under investigation (NCT03469674).

805P Clinically actionable alterations in adolescents and young adults (AYA) with gynaecological cancers

Gynecologic cancers in AYA are rare and research efforts to discover their distinct cancer biology are limited. Uncommon and aggressive subtypes of gynecologic cancer, such as mucinous and small cell ovarian carcinoma, are more frequent in AYA.

Loss of synergistic transcriptional feedback loops drives diverse B-cell cancers.

BackgroundThe most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping “cell-of-origin”. Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry.MethodsWe compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays).FindingsFrom the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation.InterpretationOur study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma.FundingNational Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.

Intra-Tumor Heterogeneity Revealed by Mass Spectrometry Imaging Is Associated with the Prognosis of Breast Cancer.

Simple SummaryThe coexistence of genetically distinct cancer cell clones, their phenotypic plasticity, and the presence of different constituents of the tumor microenvironment create intra-tumor heterogeneity, which affects cancer development and its response to therapy. We observed that a higher degree of phenotypic heterogeneity revealed by mass spectrometry imaging was associated with a favorable outcome in HER2-positive breast cancer. This phenomenon putatively reflects the presence of heterotypic components of the microenvironment, which could facilitate the response to anticancer treatment.Intra-tumor heterogeneity (ITH) results from the coexistence of genetically distinct cancer cell (sub)populations, their phenotypic plasticity, and the presence of heterotypic components of the tumor microenvironment (TME). Here we addressed the potential association between phenotypic ITH revealed by mass spectrometry imaging (MSI) and the prognosis of breast cancer. Tissue specimens resected from 59 patients treated radically due to the locally advanced HER2-positive invasive ductal carcinoma were included in the study. After the on-tissue trypsin digestion of cellular proteins, peptide maps of all cancer regions (about 380,000 spectra in total) were segmented by an unsupervised approach to reveal their intrinsic heterogeneity. A high degree of similarity between spectra was observed, which indicated the relative homogeneity of cancer regions. However, when the number and diversity of the detected clusters of spectra were analyzed, differences between patient groups were observed. It is noteworthy that a higher degree of heterogeneity was found in tumors from patients who remained disease-free during a 5-year follow-up (n = 38) compared to tumors from patients with progressive disease (distant metastases detected during the follow-up, n = 21). Interestingly, such differences were not observed between patients with a different status of regional lymph nodes, cancer grade, or expression of estrogen receptor at the time of the primary treatment. Subsequently, spectral components with different abundance in cancer regions were detected in patients with different outcomes, and their hypothetical identity was established by assignment to measured masses of tryptic peptides identified in corresponding tissue lysates. Such differentiating components were associated with proteins involved in immune regulation and hemostasis. Further, a positive correlation between the level of tumor-infiltrating lymphocytes and heterogeneity revealed by MSI was observed. We postulate that a higher heterogeneity of tumors with a better prognosis could reflect the presence of heterotypic components including infiltrating immune cells, that facilitated the response to treatment.

Exploring novel and potent molecules for disrupting DEPTOR-mTOR interaction through structure-steered screening, extra-exactitude molecular docking, prime binding free energy estimation and voguish molecular dynamics

Dep domain containing mTOR interacting protein (DEPTOR) has critical implications in the development and progression of human malignancies. Increased expression of DEPTOR promotes the growth of tumor cells by inhibiting the mTORC1, which alleviates the negative feedback inhibition by mTORC1 downstream target S6Ks on PI3K/AKT pathway thereby promotes cell survival and prevents apoptosis. This clearly suggests that targetting DEPTOR-mTOR interactions through small molecules may prove as an effective strategy for circumventing distinct cancers. In this study, we employed a top-down approach for finding three novel molecules which may prove effective in disrupting Deptor–mTOR interaction. Following DEPTOR modelling and validation we performed grid-directed structure-based screening by specifying the residues of DEPTOR known to interact with mTOR. A library of 10,000 protein–protein disrupting molecules was screened against the defined region of DEPTOR. From the screened molecules, 30 molecules with highest binding affinity were chosen for molecular docking. Thirty (30) extra-precision molecular docking experiments and 30 molecular mechanics generalized born surface area (MMGBSA) assays were performed. Following this top 10 molecules in terms of binding affinity were selected and the interaction profile of their corresponding docked files was generated. The top three molecules were finally selected after taking all the three parameters including docking score, binding energy value and interaction profile into consideration. For atomistic insights regarding DEPTOR-topmost hit interactions, molecular dynamics was performed for 100 ns. This molecule after further evaluation may prove as promising candidate for anticancer therapy. Communicated by Ramaswamy H. Sarma

Convolutional neural network in proteomics and metabolomics for determination of comorbidity between cancer and schizophrenia

The association between cancer risk and schizophrenia is widely debated. Despite many epidemiological studies, there is still no strong evidence regarding the molecular basis for the comorbidity between these two pathological conditions. The vast majority of assays have been performed using clinical records of schizophrenic patients or those undergoing cancer treatment and monitored for sufficient time to find shared features between the considered conditions. We performed mass spectrometry-based proteomic and metabolomic investigations of patients with different cancer phenotypes (breast, ovarian, renal, and prostate) and patients with schizophrenia. The resulting vast quantity of proteomic and metabolomic data were then processed using systems biology and one-dimensional (1D) convolutional neural network (1DCNN) machine learning approaches. Traditional systematic approaches permit the segregation of schizophrenia and cancer phenotypes on the level of biological processes, while 1DCNN recognized “signatures” that could segregate distinct cancer phenotypes and schizophrenia at the comorbidity level. The designed network efficiently discriminated unrelated pathologies with a model accuracy of 0.90 and different subtypes of oncophenotypes with an accuracy of 0.94. The proposed strategy integrates systematic analysis of identified compounds and application of 1DCNN model for unidentified ones to reveal the similarity between distinct phenotypes.