Periodic Reporting for period 1 - IEOCCD (THE IMPACT OF THE ENVIRONMENT AND ONCOGENESIS ON CANCER CELL DIVISIONS)
Período documentado: 2019-05-01 hasta 2021-04-30
• What is the problem/issue being addressed?
During cancer progression, cells encounter a range of complex environments. In a growing tumor, cells are exposed to soluble factors secreted by their neighbors, increased interstitial pressure, and hyplasia-induced over-crowding. The project seeks to test the hypothesis that oncogenic activation of the Ras-ERK pathway helps cancer cells proliferate despite the challenging and changing physical environments of the tumor.
• Why is it important for society?
Cancer metastasis depends on cancer cells being robust to changes in their environment. Previous approaches to study ERK dynamics and cancer cell division are done in traditional cell culture systems that do not recapitulate the mechanical environment of cancer cells in vivo. To understand and treat cancer, it would be better to study cell division and cancer cell signaling in environments that mimic those in tumors, which can be used to guide therapeutic approaches towards treating cancer. This is the aim of this work.
• What are the overall objectives?
The overall objectives of the project are:
1) How are ERK dynamics regulated during mitotic progression and what are the downstream effects?
2) How does the cancer microenvironment alter ERK dynamics and mechanism of cell division?
3) How does oncogenic activation through the Ras-ERK signaling pathway alter ERK dynamics and cell mechanics to alter the environmental sensitivity of cancer cell divisions?
During cancer progression, cells encounter a range of complex environments. In a growing tumor, cells are exposed to soluble factors secreted by their neighbors, increased interstitial pressure, and hyplasia-induced over-crowding. The project seeks to test the hypothesis that oncogenic activation of the Ras-ERK pathway helps cancer cells proliferate despite the challenging and changing physical environments of the tumor.
• Why is it important for society?
Cancer metastasis depends on cancer cells being robust to changes in their environment. Previous approaches to study ERK dynamics and cancer cell division are done in traditional cell culture systems that do not recapitulate the mechanical environment of cancer cells in vivo. To understand and treat cancer, it would be better to study cell division and cancer cell signaling in environments that mimic those in tumors, which can be used to guide therapeutic approaches towards treating cancer. This is the aim of this work.
• What are the overall objectives?
The overall objectives of the project are:
1) How are ERK dynamics regulated during mitotic progression and what are the downstream effects?
2) How does the cancer microenvironment alter ERK dynamics and mechanism of cell division?
3) How does oncogenic activation through the Ras-ERK signaling pathway alter ERK dynamics and cell mechanics to alter the environmental sensitivity of cancer cell divisions?
During the duration of the project, the following work was performed:
• Developed a pneumatic micro-scale cell confinement device to study the effects of mechanical confinement on cells
• Developed mammalian cell lines to study ERK protein activity in MCF10A epithelial cells
• Studied the effects of physical confinement on cancer cell shape during division in normal and Ras-ERK activated MCF10A cells
Findings of the project include:
• Confinement of MCF10A cells and cell rupture lead to burst of calcium signaling which cause cytoplasmic to nuclear translocation of ERK [Unpublished]
• Ras-ERK activation promotes mitotic rounding under physical confinement [Published in Matthews et al https://doi.org/10.1016/j.devcel.2020.01.004]
The findings in this project were disseminated to local and international audiences including:
• UCL-MRC LMCB Internal Seminar, 2019 [Oral Presentation]
• Cytoskeletal Club, with >100 members across >10 universities and research institutes from London, 2019 [Oral Presentation]
• Cancer Research UK-AACR Joint Conference: Engineering And Physical Science in Oncology, 2019 [Poster presentation]
• Developed a pneumatic micro-scale cell confinement device to study the effects of mechanical confinement on cells
• Developed mammalian cell lines to study ERK protein activity in MCF10A epithelial cells
• Studied the effects of physical confinement on cancer cell shape during division in normal and Ras-ERK activated MCF10A cells
Findings of the project include:
• Confinement of MCF10A cells and cell rupture lead to burst of calcium signaling which cause cytoplasmic to nuclear translocation of ERK [Unpublished]
• Ras-ERK activation promotes mitotic rounding under physical confinement [Published in Matthews et al https://doi.org/10.1016/j.devcel.2020.01.004]
The findings in this project were disseminated to local and international audiences including:
• UCL-MRC LMCB Internal Seminar, 2019 [Oral Presentation]
• Cytoskeletal Club, with >100 members across >10 universities and research institutes from London, 2019 [Oral Presentation]
• Cancer Research UK-AACR Joint Conference: Engineering And Physical Science in Oncology, 2019 [Poster presentation]
As part of the project, the fellow established and promoted the use of a micro-fabrication user group at the UCL-MRC LMCB Institute. As a result this action led to:
• Introducing micro-fabrication techniques to the Institute members who would not have been exposed to it otherwise
• A 1 day workshop was held and attended by >5 users who are novices to micro-fabrication
The fellow participated in hosting one undergraduate student and two high school students who had no prior research experience. The high school students were hosted as part of the In2scienceUK programme which promotes social mobility and diversity in STEM for low income students.
• Introducing micro-fabrication techniques to the Institute members who would not have been exposed to it otherwise
• A 1 day workshop was held and attended by >5 users who are novices to micro-fabrication
The fellow participated in hosting one undergraduate student and two high school students who had no prior research experience. The high school students were hosted as part of the In2scienceUK programme which promotes social mobility and diversity in STEM for low income students.