Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Inquiry in University Mathematics Teaching and Learning. The Platinum Project

The book presents developmental outcomes from an EU Erasmus+ project involving eight partner universities in seven countries in Europe. Its focus is the development of mathematics teaching and learning at university level to enhance the learning of mathematics by university students. Its theoretical focus is inquiry-based teaching and learning. It bases all activity on a three-layer model of inquiry: (1) Inquiry in mathematics and in the learning of mathematics in lecture, tutorial, seminar or workshop, involving students and teachers; (2) Inquiry in mathematics teaching involving teachers exploring and developing their own practices in teaching mathematics; (3) Inquiry as a research process, analysing data from layers (1) and (2) to advance knowledge inthe field. As required by the Erasmus+ programme, it defines Intellectual Outputs (IOs) that will develop in the project. PLATINUM has six IOs: The Inquiry-based developmental model; Inquiry communities in mathematics learning and teaching; Design of mathematics tasks and teaching units; Inquiry-based professional development activity; Modelling as an inquiry process; Evalutation of inquiry activity with students. The project has developed Inquiry Communities, in each of the partner groups, in which mathematicians and educators work together in supportive collegial ways to promote inquiry processes in mathematics learning and teaching. Through involving students in inquiry activities, PLATINUM aims to encourage students‘ own in-depth engagement with mathematics, so that they develop conceptual understandings which go beyond memorisation and the use of procedures. Indeed the eight partners together have formed an inquiry community, working together to achieve PLATINUM goals within the specific environments of their own institutions and cultures. Together we learn from what we are able to achieve with respect to both common goals and diverse environments, bringing a richness of experience and learning to this important area of education. Inquiry communities enable participants to address the tensions and issues that emerge in developmental processes and to recognise the critical nature of the developmental process. Through engaging in inquiry-based development, partners are enabled and motivated to design activities for their peers, and for newcomers to university teaching of mathematics, to encourage their participation in new forms of teaching, design of teaching, and activities for students. Such professional development design is an important outcome of PLATINUM. One important area of inquiry-based activity is that of „modelling“ in mathematics. Partners have worked together across the project to investigate the nature of modelling activities and their use with students. Overall, the project evaluates its activity in these various parts to gain insights to the sucess of inquiry based teaching, learning and development as well as the issues and tensions that are faced in putting into practice its aims and goals

Inquiry in University Mathematics Teaching and Learning

The book presents developmental outcomes from an EU Erasmus+ project involving eight partner universities in seven countries in Europe. Its focus is the development of mathematics teaching and learning at university level to enhance the learning of mathematics by university students. Its theoretical focus is inquiry-based teaching and learning. It bases all activity on a three-layer model of inquiry: (1) Inquiry in mathematics and in the learning of mathematics in lecture, tutorial, seminar or workshop, involving students and teachers; (2) Inquiry in mathematics teaching involving teachers exploring and developing their own practices in teaching mathematics; (3) Inquiry as a research process, analysing data from layers (1) and (2) to advance knowledge inthe field. As required by the Erasmus+ programme, it defines Intellectual Outputs (IOs) that will develop in the project. PLATINUM has six IOs: The Inquiry-based developmental model; Inquiry communities in mathematics learning and teaching; Design of mathematics tasks and teaching units; Inquiry-based professional development activity; Modelling as an inquiry process; Evalutation of inquiry activity with students. The project has developed Inquiry Communities, in each of the partner groups, in which mathematicians and educators work together in supportive collegial ways to promote inquiry processes in mathematics learning and teaching. Through involving students in inquiry activities, PLATINUM aims to encourage students` own in-depth engagement with mathematics, so that they develop conceptual understandings which go beyond memorisation and the use of procedures. Indeed the eight partners together have formed an inquiry community, working together to achieve PLATINUM goals within the specific environments of their own institutions and cultures. Together we learn from what we are able to achieve with respect to both common goals and diverse environments, bringing a richness of experience and learning to this important area of education. Inquiry communities enable participants to address the tensions and issues that emerge in developmental processes and to recognise the critical nature of the developmental process. Through engaging in inquiry-based development, partners are enabled and motivated to design activities for their peers, and for newcomers to university teaching of mathematics, to encourage their participation in new forms of teaching, design of teaching, and activities for students. Such professional development design is an important outcome of PLATINUM. One important area of inquiry-based activity is that of “modelling” in mathematics. Partners have worked together across the project to investigate the nature of modelling activities and their use with students. Overall, the project evaluates its activity in these various parts to gain insights to the sucess of inquiry based teaching, learning and development as well as the issues and tensions that are faced in putting into practice its aims and goals

Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. Methods: To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1?/?;p53?/?, Brca2?/?;p53?/? and p53?/? mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Results: Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYCassociated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2?/?;p53?/? tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. Conclusions: The selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.MediamaticsElectrical Engineering, Mathematics and Computer Scienc

Publisher Correction: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

This paper was originally published under a standard Springer Nature license

Body dysmorphia in common skin diseases: Results of an observational, cross-sectional multi-centre study among dermatological out-patients in 17 European countries

Background Body dysmorphic disorder (BDD) is a common psychiatric disorder associated with high costs for healthcare systems as patients may repeatedly ask for different, often not effective interventions. BDD symptoms are more prevalent in patients with dermatological conditions than the general population, but there are no large sample studies comparing the prevalence of BDD symptoms between patients with dermatological conditions and healthy skin controls. Objectives To compare the prevalence of BDD symptoms between patients with different dermatological conditions and healthy skin controls and to describe sociodemographic, physical and psychological factors associated with BDD symptoms to identify patients who may have a particularly high chance of having this condition. Methods This observational cross-sectional, comparative multi-centre study included 8295 participants: 5487 consecutive patients with different skin diseases (56% female) recruited among dermatological out-patients at 22 clinics in 17 European countries and 2808 healthy skin controls (66% female). All patients were examined by a dermatologist. BDD symptoms were assessed by the Dysmorphic Concern Questionnaire (DCQ). Sociodemographic data, information on psychological factors and physical conditions were collected. Each patient was given a dermatological diagnosis according to ICD-10 by a dermatologist. Results The participation rate of invited dermatological patients was 82.4% on average across all centres. BDD symptoms were five times more prevalent in patients with dermatological conditions than in healthy skin controls (10.5% vs. 2.1%). Patients with hyperhidrosis, alopecia and vitiligo had a more than eleven-fold increased chance (adjusted Odds Ratio (OR) > 11) of having BDD symptoms compared to healthy skin controls, and patients with atopic dermatitis, psoriasis, acne, hidradenitis suppurativa, prurigo and bullous diseases had a more than six-fold increased chance (adjusted OR > 6) of having BDD symptoms. Using a logistic regression model, BDD symptoms were significantly related to lower age, female sex, higher psychological stress and feelings of stigmatisation. Conclusions This study reveals that clinical BDD symptoms are significantly associated with common dermatological diseases. As such symptoms are associated with higher levels of psychological distress and multiple unhelpful consultations, general practitioners and dermatologists should consider BDD and refer patients when identified to an appropriate service for BDD screening and management