Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant ...sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
ABSTRACT
High‐resolution monthly precipitation climatologies for Italy are presented. They are based on 1961–1990 precipitation normals obtained from a quality‐controlled dataset of 6134 stations ...covering the Italian territory and part of the Northern neighbouring regions. The climatologies are computed by means of two interpolation methods modelling the precipitation‐elevation relationship at a local level, more precisely a local weighted linear regression (LWLR) and a local regression kriging (RK) are performed. For both methods, local optimisations are also applied in order to improve model performance. Model results are compared with those provided by two other widely used interpolation methods which do not consider elevation in modelling precipitation distribution: ordinary kriging and inverse distance weighting. Even though all the four models produce quite reasonable results, LWLR and RK show the best agreement with the observed station normals and leave‐one‐out‐estimated mean absolute errors ranging from 5.1 mm (July) to 11 mm (November) for both models. Their better performances are even clearer when specific clusters of stations (e.g. high‐elevation sites) are considered. Even though LWLR and RK provide very similar results both at station and at grid point level, they show some peculiar features. In particular, LWLR is found to have a better extrapolation ability at high‐elevation sites when data density is high enough, while RK is more robust in performing extrapolation over areas with complex orography and scarce data coverage, where LWLR may provide unrealistic precipitation values. However, by means of prediction intervals, LWLR provides a more straightforward approach to quantify the model uncertainty at any point of the study domain, which helps to identify the areas mainly affected by model instability. LWLR and RK high‐resolution climatologies exhibit a very heterogeneous and seasonal‐dependent precipitation distribution throughout the domain and allow to identify the main climatic zones of Italy.
The paper presents high‐resolution monthly precipitation climatologies for Italy. They are computed by means of two interpolation methods modelling the precipitation‐elevation relationship at a local level: local weighted linear regression (LWLR) and regression kriging (RK). The monthly errors turn out to range from 5 mm to 11 mm for both models. LWLR shows a better extrapolation ability at high‐elevated sites, while RK is preferable over areas with complex orography and scarce data coverage, where LWLR may provide unrealistic precipitation values.
The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on ...tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.
Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast ...cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.
Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the ...transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial-mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 3'-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. Finally, we show that the loss of BTG2 expression confers to non-tumorigenic prostate cells ability to grow in an orthotopic murine model, thus demonstrating the central role of BTG2 downregulaton in prostate cancer biology.
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to ...NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
Abstract The checkpoint kinase 1 (Chk1) is a key component of the DNA damage response, a molecular network deputed to maintain genome integrity. Nevertheless, cancer cells aberrantly exploit these ...circuits to overcome chemotherapy-induced cytotoxicity. Chk1 inhibitors have been developed as a chemopotentiating strategy and different molecular mechanisms underlying the synergism with chemotherapeutics have been uncovered. The monotherapy with Chk1 inhibitors seems to be endowed with antitumor activity against cancer cells characterized by specific defects in the DNA damage machinery or characterized by elevated levels of oncogene-induced replication stress. In this biological framework Chk1 neutralization represents a synthetic lethality-based therapeutic approach. Moreover, a dual targeting of the DNA damage machinery has been proposed envisioning the association of Chk1 abrogation with poly-ADP ribose polymerase inhibitors. The spectrum of antitumor properties of Chk1 antagonists is completed by the activity against cancer stem cells, the prominent tumorigenic population that is equipped to survive stressful conditions through multiple and interconnected mechanisms. Although the clinical development of the first generation of Chk1 antagonists was hindered by off-target effects and an unfavorable pharmacokinetic profile, a new wave of early clinical trials with more selective compounds are currently being carried out. To this end, the identification of predictive biomarkers and an in-depth characterization of molecular circuits governed by Chk1 are issues that need to be addressed for sharpening the therapeutic potential of Chk1 inhibitors.
ABSTRACT
High‐resolution monthly temperature climatologies for Italy are presented. They are based on a dense and quality‐controlled observational dataset which includes 1484 stations and on three ...distinct approaches: multi‐linear regression with local improvements (MLRLI), an enhanced version of the model recently used for the Greater Alpine Region, regression kriging (RK), widely used in literature and, lastly, local weighted linear regression (LWLR) of temperature versus elevation, which may be considered more suitable for the complex orography characterizing the Italian territory.
Dataset and methods used both to check the station records and to get the 1961–1990 normals used for the climatologies are discussed. Advantages and shortcomings of the three approaches are investigated and the results are compared.
All three approaches lead to quite reasonable models of station temperature normals, with lowest errors in spring and autumn and highest errors in winter. The LWLR approach shows slightly better performances than the other two, with monthly leave‐one‐out estimated root mean square errors ranging from 0.74 °C (April and May) to 1.03 °C (December). Further evidence in its favour is the greater reliability of local approach in modelling the behaviour of the temperature‐elevation relationship in Italy's complex territory.
The comparison of the different climatologies is a very effective tool to understand the robustness of each approach. Moreover, the first two methods (MLRLI and RK) turn out to be important to tune the third one (LWLR), as they help not only to understand the relationship between temperature normals and some important physiographical variables (MLRLI) but also to study the decrease of station normals covariance with distance (RK).
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