Periodic Reporting for period 1 - NOSCAR (decipheriNg Oncogenic SIgnalling patterns to break CAncer drug Resistance)
Okres sprawozdawczy: 2020-09-01 do 2023-08-31
Breast cancer is the leading cancer in women by incidence and the second cause of cancer-related death in the female population. To cure the more advanced and aggressive cases of breast cancer, modern, targeted therapies have been proposed. However, cancer drug resistance limits the premise of targeted therapy. The project “Deciphering oncogenic signalling patterns to break cancer drug resistance” - NOSCAR - aimed to better understand how a specific type of breast cancer develops resistance to targeted therapies. The project asked how specific oncogenic mutations – the molecular causes of cancer – reprogramme information flow in the epithelial tissue, how mutation-reprogrammed tissue responds to standard drug treatments, how cancer cells interact with one another to escape these treatments and develop resistance, and how such interaction can be prevented to break cancer resistance to targeted therapy?
Drug resistance in cancer is an unsolved problem in oncology and new therapy options are urgently needed to meet patient’s needs. In alignment with the EU’s Cancer Mission, NOSCAR addressed tissue-scale mechanisms of PIK3CA-mutated cancer resistance to therapies. It is expected that the study findings will prompt the development of more effective, less resistance-prone, and less toxic breast cancer treatments, and possibly, other types of epithelial cancers carrying PIK3CA mutations. This would largely benefit the societal needs – cancer patients and their families – to cure cancer or improve patient condition and quality of life with the disease.
This Marie Skłodowska Curie Action (MSCA) aimed to define oncogenic cellular communication at the single cell resolution and delineate the mechanisms, which enable development of cancer resistance to targeted therapies. The 3 key objectives of NOSCAR were (1) to identify how a panel of clinically-relevant cancer causing mutations reprogramme cellular communication in a breast epithelium; (2) to define how a drug compendium targeting tumour affects information flow / cancer cell communication and what are potential escape mechanisms that cancer cells use to resist the treatment; and finally, to (3) test the findings of objective 2 and 3 in patient-derived organoids (PDOs) – miniature three-dimensional models of organs grown in a laboratory from a small sample of a patient's tissue.
Drug resistance in cancer is an unsolved problem in oncology and new therapy options are urgently needed to meet patient’s needs. In alignment with the EU’s Cancer Mission, NOSCAR addressed tissue-scale mechanisms of PIK3CA-mutated cancer resistance to therapies. It is expected that the study findings will prompt the development of more effective, less resistance-prone, and less toxic breast cancer treatments, and possibly, other types of epithelial cancers carrying PIK3CA mutations. This would largely benefit the societal needs – cancer patients and their families – to cure cancer or improve patient condition and quality of life with the disease.
This Marie Skłodowska Curie Action (MSCA) aimed to define oncogenic cellular communication at the single cell resolution and delineate the mechanisms, which enable development of cancer resistance to targeted therapies. The 3 key objectives of NOSCAR were (1) to identify how a panel of clinically-relevant cancer causing mutations reprogramme cellular communication in a breast epithelium; (2) to define how a drug compendium targeting tumour affects information flow / cancer cell communication and what are potential escape mechanisms that cancer cells use to resist the treatment; and finally, to (3) test the findings of objective 2 and 3 in patient-derived organoids (PDOs) – miniature three-dimensional models of organs grown in a laboratory from a small sample of a patient's tissue.
Work was carried out in 6 work packages (WPs). WP1 identified how a panel of clinically relevant cancer-associated mutations reprogram cellular communication in breast epithelium. This comprised preparing a working model - introducing biosensors to prototype cancer models, setting up image acquisition, image quantification and data analysis pipelines, and acquiring the data. This allowed to identify mutation-specific pathological cellular signalling patterns. We found that a large part of this network is based on cell-cell communication across the tissue. This demonstrates that in tested cancer models oncogenic signalling is a tissue-scale property. This yielded data for 3 conference presentations including EACR Congress –the major cancer research conference in Europe.
WP2 aimed to identify how mutation-reprogrammed epithelium responds to standard drug treatments. We found that mutation-reprogrammed epithelial tissue capitalizes on fundamental epithelial homeostasis mechanisms to grow uncontrollably and resist targeted therapy. These findings so far resulted in 4 conference presentations, 3 of which were selected for conference talks. In addition, part of the work carried in WP2 contributed to peer-reviewed journal publication (Mol Syst Biol) and yielded datasets for the development of image quantification/analysis methods.
WP3 explored oncogenic mutation-reprogrammed tissue properties in three-dimensional in vitro models. This involved studies using the reductionist MCF10A mammary morphogenesis model and patient-derived organoids. The studies on the MCF10A spheroid model demonstrated that increased cell-cell communication allows cancer cells to escape programmed cell death and distorts mammary gland architecture, allowing uncontrolled growth. The planned work on PDOs was substituted with work on genetically modified mouse organoids (due to a lack of suitable PDOs from the biobank) and is still ongoing through external collaboration. The results of this part of the study so far contributed to 1 peer-reviewed journal publication (Dev Cell), and 1 publication in preparation that will combine the major findings of WP1, WP2, and WP3.
In WP4 the fellow received extensive technical training through the implementation of NOSCAR in the host laboratory – a laboratory with strong expertise in spatiotemporal bioimaging and quantitative image analysis. The fellow gained expertise in advanced imaging, computer vision-based image quantification, biosensor technology, and analysis of large datasets using computational and statistical methods. In addition, the fellow gained knowledge in breast cancer and received advanced training in applications of organoid technologies and techniques for mammary gland research at EMBL.
The WP5 focused on transferable skills for career development. The fellow completed COMET - Coaching, Mentoring, and Training – University of Bern’s Career Programme and received leadership, project management, and fund acquisition training. In addition, she co-supervised junior researchers (1 master's student, 1 bachelor's student, and 1 doctoral student), and was involved in grant writing. Beyond providing new skills, the training activities of WP4 and WP5 greatly added to the growth of fellow’s professional network.
In WP6 the fellow disseminated and communicated the research to the public, and scientific community. The fellow took an active part in popularising science through science outreach events “Science is Wonderful!” and “Research Night” at the University of Bern. She presented her research at 8 international conferences and workshops and coauthored 2 research articles.
WP2 aimed to identify how mutation-reprogrammed epithelium responds to standard drug treatments. We found that mutation-reprogrammed epithelial tissue capitalizes on fundamental epithelial homeostasis mechanisms to grow uncontrollably and resist targeted therapy. These findings so far resulted in 4 conference presentations, 3 of which were selected for conference talks. In addition, part of the work carried in WP2 contributed to peer-reviewed journal publication (Mol Syst Biol) and yielded datasets for the development of image quantification/analysis methods.
WP3 explored oncogenic mutation-reprogrammed tissue properties in three-dimensional in vitro models. This involved studies using the reductionist MCF10A mammary morphogenesis model and patient-derived organoids. The studies on the MCF10A spheroid model demonstrated that increased cell-cell communication allows cancer cells to escape programmed cell death and distorts mammary gland architecture, allowing uncontrolled growth. The planned work on PDOs was substituted with work on genetically modified mouse organoids (due to a lack of suitable PDOs from the biobank) and is still ongoing through external collaboration. The results of this part of the study so far contributed to 1 peer-reviewed journal publication (Dev Cell), and 1 publication in preparation that will combine the major findings of WP1, WP2, and WP3.
In WP4 the fellow received extensive technical training through the implementation of NOSCAR in the host laboratory – a laboratory with strong expertise in spatiotemporal bioimaging and quantitative image analysis. The fellow gained expertise in advanced imaging, computer vision-based image quantification, biosensor technology, and analysis of large datasets using computational and statistical methods. In addition, the fellow gained knowledge in breast cancer and received advanced training in applications of organoid technologies and techniques for mammary gland research at EMBL.
The WP5 focused on transferable skills for career development. The fellow completed COMET - Coaching, Mentoring, and Training – University of Bern’s Career Programme and received leadership, project management, and fund acquisition training. In addition, she co-supervised junior researchers (1 master's student, 1 bachelor's student, and 1 doctoral student), and was involved in grant writing. Beyond providing new skills, the training activities of WP4 and WP5 greatly added to the growth of fellow’s professional network.
In WP6 the fellow disseminated and communicated the research to the public, and scientific community. The fellow took an active part in popularising science through science outreach events “Science is Wonderful!” and “Research Night” at the University of Bern. She presented her research at 8 international conferences and workshops and coauthored 2 research articles.
The project findings demonstrate the importance of tissue-scale mechanisms in the development of cancer drug resistance. This is a new frontier in (cancer) biology. The findings highlight the advantages of the spatiotemporal quantitative biology approach to understanding system-level cellular and molecular mechanisms that facilitate drug resistance in cancer. The methods, trained machine-learning models, computational tools, and data analysis scripts developed during the project will benefit the broad scientific community. NOSCAR explains why some current treatment options (targeted therapy) have limited effectiveness and proposes new, rational-based targeting strategies. This might result in more effective, less resistance-prone, and less toxic breast cancer treatments for a large fraction of breast cancer patients, as well as other types of PIK3CA-mutated epithelial cancers, which would add to the ultimate goal of improving cancer patient condition and curing cancer.
New connections with schools made during outreach activities will facilitate further communication to de-mystify and popularise scientists’ profession and increase interest in STEM (especially among girls).
The planned research together with training and mentoring that the fellow received thanks to the fellowship, enabled the successful restart of the fellow’s career in research and significantly benefited her further career prospects.
New connections with schools made during outreach activities will facilitate further communication to de-mystify and popularise scientists’ profession and increase interest in STEM (especially among girls).
The planned research together with training and mentoring that the fellow received thanks to the fellowship, enabled the successful restart of the fellow’s career in research and significantly benefited her further career prospects.