Organoid model of mammographic density displays a higher frequency of aberrant colony formations with radiation exposure
Year: 2019
Type: article
Abstract: MOTIVATION: Aberrant three-dimensional (3D) colony organization of premalignant human mammary epithelial cells (HMECs) is one of the indices of dysplasia. An experiment has been designed where the stiffness of the microenvironment, in 3D culture, has been set at either low or high level of mammographic density (MD) and the organoid models are exposed to 50 cGy X-ray radiation. This study utilizes published bioinformatics tools to quantify the frequency of aberrant colony formations by the combined stressors of stiffness and X-ray exposure. One of the goals is to develop a quantitative assay for evaluating the risk factors associated with women with high MD exposed to X-ray radiation. RESULTS: Analysis of 3D colony formations indicate that high stiffness, within the range of high MD, and X-ray radiation have an approximately additive effect on increasing the frequency of aberrant colony formations. Since both stiffness and X-ray radiation are DNA-damaging stressors, the additive effect of these stressors is also independently validated by profiling activin A-secreted protein. Secretion of activin A is known to be higher in tissues with a high MD as well as tumor cells. In addition, we show that increased stiffness of the microenvironment also induces phosphorylation of γH2AX-positive foci. The study uses two HMECs derived from a diseased tissue (e.g. MCF10A) and reduction mammoplasty of normal breast tissue (e.g. 184A1) to further demonstrate similar traits in the frequency of aberrant colony organization. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Source: Bioinformatics
Authors: Qingsu Cheng, Bahram Parvin
Institution: University of Nevada, Reno
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: DURING SPACE TRAVEL ASTRONAUTS WILL EXPERIENCE A UNIQUE ENVIRONMENT THAT INCLUDES CONTINUOUS EXPOSURE TO MICROGRAVITY AND STRESSFULLIVING CONDITIONS. PHYSIOLOGICAL ADAPTATION TO THIS IS A CHALLENGE AND THE EFFECT OF MICROGRAVITY ON ORGAN DEVELOPMENT ARCHITECTURE AND FUNCTION IS NOT WELL UNDERSTOOD. HOW MICROGRAVITY MAY IMPACT THE GROWTH AND DEVELOPMENT OF AN ORGAN IS AN IMPORTANTISSUE ESPECIALLY AS SPACE FLIGHT BECOMES MORE COMMONPLACE. THESE FUNDAMENTAL QUESTIONS CAN BE ADDRESSED BY STUDYING SIMULATEDMICROGRAVITY EXPOSED CELLS IN VITRO. 3D TISSUE CULTURE MODELS MIMICKING MAMMARY GLAND STRUCTURES HAVE BEEN OPTIMIZED AND CANBE USED TO DEFINE IF EXPOSED CELLS CAN CORRECTLY ASSEMBLE INTO THESE STRUCTURES TO ADDRESS SOME OF NASAS KEY QUESTIONS REGARDINGMICROGRAVITY EFFECTS ON CELLS AND ORGANS. ADDITIONALLY AS PROPER ACTIVATION OF STEM CELLS IS KEY TO ORGAN FORMATION IT IS IMPORTANTTO DEFINE HOW MICROGRAVITY MAY AFFECT THESE SPECIALIZED CELLS. IN THE PROPOSED WORK WE WILL EXPOSE A MAMMARY EPITHELIAL CELL LINE(COMMA 1D) KNOWN TO CONTAIN A HIGH PROPORTION OF STEM CELLS AND QUANTIFY THE CHANGES IN MAMMARY STEM CELL POPULATIONS BEFORE ANDAFTER MICROGRAVITY EXPOSURE. FURTHER WE WILL IDENTIFY HOW EXPOSURE TO SIMULATED MICROGRAVITY AFFECTS THE CELLS ABILITY TO FORM NORMAL3D STRUCTURES IMPORTANT IN MAMMARY ORGAN DEVELOPMENT FOLLOWING THIS EXPOSURE. IN ADDITION WE WILL TEST ROLE OF GENETICS BY ISOLATINGMOUSE MAMMARY EPITHELIAL CELLS FROM MICE SHOWING INCREASED AND REDUCED SENSITIVITIES TO CANCER TO DEFINE IF SIMULATED MICROGRAVITYSHOWS DIFFERENTIAL EFFECTS DEPENDENT ON UNDERLYING GENETICS. NEXT WE WILL IDENTIFY MIRNA CHANGES IN STEM CELLS ISOLATED PRE AND POSTSIMULATED MICROGRAVITY EXPOSURE TO DEFINE THE UNDERLYING MOLECULAR REASONS FOR DEFECTS IN CORRECT 3D STRUCTURE FORMATION. A FINALAIM WILL BE TO DEFINE WHETHER MICROGRAVITY IN COMBINATION WITH CERTAIN GENETIC BACKGROUNDS CAUSES CELLULAR CHANGES INDICATIVE OF ANINCREASED CANCER RISK. WE HYPOTHESIZE THAT CELLS EXPOSED TO SIMULATED MICROGRAVITY AND ASSAYED IN 3D WILL ALLOW US TO DEFINE HOW THISEXPOSURE WOULD IMPACT THE GROWTH AND DEVELOPMENT OF THE MAMMARY GLAND IN VIVO. WE FURTHERMORE HYPOTHESIZE THAT THE MAGNITUDEOF THIS RESPONSE DEPENDS UPON GENETIC SUSCEPTIBILITY AND THUS WILL UTILIZE CELLS FROM DIFFERENT MOUSE STRAINS TO INVESTIGATE THIS (CANCERPRONE AND RESISTANT). LASTLY WE HYPOTHESIZE THAT THE SIMULATED MICROGRAVITY EXPOSURE IN AN AT RISK GENETIC BACKGROUND MAY CAUSECHANGES IN CELLS THAT INCREASE THE PROPENSITY TO DEVELOP CANCER. THESE STUDIES WILL HELP IDENTIFY THE CELLULAR AND MOLECULAR CHANGES ANDUNDERLYING GENETIC MECHANISMS OF SIMULATED MICROGRAVITY AND HOW IT IMPACTS OVERALL TISSUE FUNCTION., Stratifying brain tumors by structural subtyping and heterogeneity
OpenAlex ID: W2991039337