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Centrosome amplification (CA) is a common feature of human tumours and a promising target for cancer therapy. However, CA's pan-cancer prevalence, molecular role in tumourigenesis and therapeutic value in the clinical setting are still largely unexplored. Here, we used a transcriptomic signature (CA20) to characterise the landscape of CA-associated gene expression in 9,721 tumours from The Cancer Genome Atlas (TCGA). CA20 is upregulated in cancer and associated with distinct clinical and molecular features of breast cancer, consistently with our experimental CA quantification in patient samples. Moreover, we show that CA20 upregulation is positively associated with genomic instability, alteration of specific chromosomal arms and C>T mutations, and we propose novel molecular players associated with CA in cancer. Finally, high CA20 is associated with poor prognosis and, by integrating drug sensitivity with drug perturbation profiles in cell lines, we identify candidate compounds for selectively targeting cancer cells exhibiting transcriptomic evidence for CA.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) within invasive lobular carcinoma (ILC) remains to be better characterized. In estrogen receptor (ER)-negative invasive ductal carcinomas of no special type (IDC-NST), TILs are associated with good prognosis. The aim of this study was to examine TILs in ILC, with particular focus on prognostic and clinicopathologic features. A cohort comprising 459 consecutive ILCs diagnosed in a single institution from 2005 to 2008 met the eligibility criteria for this study. The percentage of tumor area occupied by TILs was quantified by two breast pathologists and categorized into three groups: no TILs, ≤5%, >5%. Clinicopathologic features were tested by Fisher's exact tests or Chi2 tests. Overall survival (OS) and invasive disease-free survival (iDFS) were estimated by Kaplan–Meier and Cox proportional hazard statistics. There were 239 TIL-negative cases, 185 cases with ≤5% TILs, and 35 cases with >5% TILs. TILs were associated with younger age, larger tumors, lymph node involvement, poor Nottingham prognostic index, HER2 amplification, multinucleation, and prominent nucleoli (p < 0.05). Poor OS was significantly associated with increasing TILs in the univariate Cox proportional hazards model (p < 0.001) and Kaplan–Meier estimator (p < 0.05, log-rank test). Similar results were observed for iDFS (p = 0.004 for Cox univariate and p = 0.005 for log-rank test). Notably, TILs can identify a subset of ILC patients with poor OS independently of molecular subtype and lymph node metastases (multivariate Cox, p < 0.001, OS hazard ratio (HR) = 4.38 and HR = 6.15, for ≤5% and >5% TILs, respectively, vs. absence of TILs). Prominent nucleoli was the only nuclear feature associated with poor OS (p = 0.05) and iDFS (p = 0.05) in univariate Cox survival analysis. TILs represent a promising new morphologic biomarker associated with poor outcome of ILC, in contrast with that observed in ER-negative IDC-NST.

Biodegradable polymers find applications in many market segments. The ability to meet mechanical requirements within a certain time range, after which it degrades and is naturally absorbed, can be used to produce short-term use products that can be easily disposable with less environmental impact. In the segment of medical devices used in regenerative medicine, these materials are used to produce temporary implants that are naturally assimilated by the human body, avoiding a removal surgery. However, the design of these temporary devices still presents great challenges, namely in the verification of the main requirement: the lifetime of the device, associated with the progressive loss of mechanical properties, until its complete erosion and assimilation. Thus, in this study, a numerical approach is proposed to simulate the polymeric device’s mechanical behavior during its hydrolytic degradation by combining the hydrolysis kinetics, that depends on mechanical factors and promotes a decrease of molecular weight and consequent decrease of mechanical performance, and erosion, when molecular weight reaches a threshold value and the polymer becomes soluble and diffuses outward, resulting in mass loss and decreasing cross-sectional area, which also contributes to the mechanical performance reduction of the device. A phenomenological approach, using the combination of continuum-based hydrolytic damage for the evolution of mechanical properties that depends on the stress field and further removal of the degraded element (to simulate mass loss) was used. Both elastoplastic and hyperelastic constitutive models were applied on this study, where the material model parameters locally depend on the molecular weight.

The aim of this work is to evaluate the changes in compression properties of a bio-based polyurethane foam after exposure to 90 °C for different periods of time, and to propose a method to extrapolate these results and use a numerical approach to predict the compression behaviour after degradation for untested conditions at different degradation times and temperatures. Bio-based polymers are an important sustainable alternative to oil-based materials. This is explained by the foaming process and the density along the material as it was possible to see in a digital image correlation analysis. After 60 days, stiffness was approximately decreased by half in both directions. The decrease in yield stress due to thermo-oxidative degradation had a minor effect in the foaming directions, changing from 352 kPa to 220 kPa after 60 days, and the transverse property was harshly impacted changing from 530 kPa to 265 kPa. The energy absorption efficiency was slightly affected by degradation. The simulation of the compression stress-strain curves were in accordance to the experimental data and made it possible to predict the changes in mechanical properties for intermediate periods of degradation time. The plateau stress for the unaged foam transverse to the foaming direction presented experimental and numerical values of 450 kPa and 470 kPa, respectively. In addition, the plateau stresses in specimens degraded for 40 days present very similar experimental and numerical results in the same direction, at 310 kPa and 300 kPa, respectively. Therefore, this paper presents important information regarding the life-span and degradation of a green PUF. It provides insights into how compression properties vary along degradation time as function of material operation temperature, according to the Arrhenius degradation equation.

Centrosomes are the major microtubule organising centres of animal cells. Deregulation in their number occurs in cancer and was shown to trigger tumorigenesis in mice. However, the incidence, consequence and origins of this abnormality are poorly understood. Here, we screened the NCI-60 panel of human cancer cell lines to systematically analyse centriole number and structure. Our screen shows that centriole amplification is widespread in cancer cell lines and highly prevalent in aggressive breast carcinomas. Moreover, we identify another recurrent feature of cancer cells: centriole size deregulation. Further experiments demonstrate that severe centriole over-elongation can promote amplification through both centriole fragmentation and ectopic procentriole formation. Furthermore, we show that overly long centrioles form over-active centrosomes that nucleate more microtubules, a known cause of invasiveness, and perturb chromosome segregation. Our screen establishes centriole amplification and size deregulation as recurrent features of cancer cells and identifies novel causes and consequences of those abnormalities. Cancer cells are characterised by abnormalities in the number of centrosomes and this phenotype is linked with tumorigenesis. Here the authors report centriole length deregulation in a subset of cancer cell lines and suggest a link with subsequent alterations in centriole numbers and chromosomal instability.

Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans , which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans , with a three-order of magnitude difference between animals fed Escherichia coli , Comamonas aquatica , and Bacillus subtilis . Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals. Here, Diot et al . use the nematode Caenorhabditis elegans as a model to identify off-target toxicity mechanisms for tamoxifen, and find that these include fatty acid metabolism and cell death, which can be modulated by different bacterial species.

Transitions between epithelial and mesenchymal cellular states (EMT/MET) contribute to cancer progression. We hypothesize that EMT followed by MET promotes cell population heterogeneity, favouring tumour growth. We developed an EMT model by on and off exposure of epithelial EpH4 cells (E-cells) to TGFβ1 that mimics phenotypic EMT (M-cells) and MET. We aimed at understanding whether phenotypic MET is accompanied by molecular and functional reversion back to epithelia by using RNA sequencing, immunofluorescence (IF), proliferation, wound healing, focus formation and mamosphere formation assays as well as cell xenografts in nude mice. Phenotypic reverted epithelial cells (RE-cells) obtained after MET induction presented epithelial morphologies and proliferation rates resembling E cells. However, the RE transcriptomic profile and IF staining of epithelial and mesenchymal markers revealed a uniquely heterogeneous mixture of cell subpopulations with a high self-renewal ability. RE cell heterogeneity was stably maintained for long periods after TGFβ1 removal both in vitro and in large tumours derived from the nude mice. Overall, we show that phenotypic reverted epithelial cells (RE cells) do not return to the molecular and functional epithelial state and present mesenchymal features related to aggressiveness and cellular heterogeneity that favour tumour growth in vivo. This work strengthens epithelial cell reprogramming and cellular heterogeneity fostered by inflammatory cues as a tumour growth-promoting factor in vivo.

Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44+CD24−/low. Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3–5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients.

A key response to glucose stress is an increased production of unsaturated fatty acids to balance the increase in saturated fatty acids in the membrane. The C. elegans homolog of stearoyl-CoA desaturase, FAT-7, introduces the first double bond into saturated C18 fatty acids yielding oleic acid, and is a critical regulatory point for surviving cold and glucose stress. Here, we incorporated 13C stable isotopes into the diet of nematodes and quantified the 13C-labelled fatty acid using GC-MS and HPLC/MS-MS to track its metabolic response to various concentrations of glucose. Previous work has analyzed the membrane composition of C. elegans when responding to mild glucose stress and showed few alterations in the overall fatty acid composition in the membrane. Here, in nematodes exposed to higher concentrations of glucose, a specific reduction in oleic acid and linoleic acid was observed. Using time courses and stable isotope tracing, the response of fatty acid metabolism to increasing levels of glucose stress is characterized, revealing the funneling of monounsaturated fatty acids to preserve the abundance of polyunsaturated fatty acids. Taken together, higher levels of glucose unveil a specific reduction in oleic and linolenic acid in the metabolic rewiring required to survive glucose stress.

Breast carcinomas (BC) with osteoclast-like giant cells (OGC) are rare. Despite their distinct stromal features, their molecular characteristics remain unknown. Here, we report comprehensive clinico-pathological and molecular findings for 27 patients diagnosed with BC-OGC at Institut Curie between 2000 and 2021. Seventeen (63%) cases were invasive carcinomas of no special type (IC NST) with OGC (OGC-IC NST), four (15%) were mixed or multifocal cases with and without OGC (OGC-Mixed), and six (22%) were metaplastic carcinomas with OGC (OGC-MC). All OGC-IC NST and OGC-Mixed cases were ER+ HER2− tumors (most being luminal A based on transcriptomic subtyping, when available), while all OGC-MC were triple-negative. The median age at diagnosis was 46, 45 and 62 years for OGC-IC NST, OGC-Mixed and OGC-MC, respectively. Three patients developed distant metastases (one OGC-IC NST, two OGC-Mixed), one of whom died of metastatic disease (OGC-Mixed), and one other patient died of locally advanced disease (OGC-MC). Histopathological evaluation comparing 13 OGC-IC NST and 19 control IC NST without OGC confirmed that OGC-IC NST showed significantly higher density of vessels (by CD34 immunohistochemistry (IHC)), iron deposits (Perls stain), and CD68 and CD163-positive cell infiltrates. Genomic findings for nine OGC-IC NST and four OGC-MC were consistent with the underlying histologic subtype, including activating alterations of the PI3K/AKT/mTOR pathway in 7/13 cases. Using RNA-seq data, differential gene expression analysis between OGC-IC NST (n = 7) and control IC NST without OGC (n = 7) revealed significant overexpression of TNFSF11 (RANK-L), TNFRSF11A (RANK), CSF1 (M-CSF), CSF1R, and genes encoding osteoclastic enzymes (MMP9, ACP5, CTSK, CTSB) in OGC-IC NST, while OPG (osteoprotegerin) was underexpressed. We also confirmed for the first time RANK-L expression in BC with OGC by IHC (seen in 15 out of 16 cases, and only in 2 of 16 controls without OGC). These findings could offer a rationale for further investigating RANK-L as a therapeutic target in BC with OGC.