TY - JOUR
T1 - Epithelial-mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation
AU - Lutgendorf, Susan K.
AU - Penedo, Frank
AU - Goodheart, Michael J.
AU - Dahmoush, Laila
AU - Arevalo, Jesusa M.G.
AU - Thaker, Premal H.
AU - Slavich, George M.
AU - Sood, Anil K.
AU - Cole, Steve W.
N1 - Funding Information:
Supported in part by National Institutes of Health grants CA193249, CA140933, CA246540 (to Susan K. Lutgendorf), CA109298, CA209904, ACS Research Professor Award (to Anil K. Sood), AG017265 and AG043404 (to Steve W. Cole), and P30CA086862 (Principal Investigator: George Weiner). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
Susan K. Lutgendorf has received grants from the National Institutes of Health for work performed as part of the current study. Frank Penedo has received grants from the National Institutes of Health for work performed as part of the current study. Michael J. Goodheart has received grants from the National Institutes of Health for work performed as part of the current study. Laila Dahmoush has received grants from the National Institutes of Health for work performed as part of the current study. Jesusa M. G. Arevalo has received grants from the National Institutes of Health for work performed as part of the current study. Premal H. Thaker has acted as a paid consultant or speaker for Stryker, Iovance Biotherapeutics, AbbVie/Stemcentrx, Clovis Oncology, Unleash Immunolytics, and Celsion Corporation; has received research funding and personal fees from Merck and GlaxoSmithKline; has received personal fees from AstraZeneca; and is a Celsion shareholder. George M. Slavich has received grants from the National Institutes of Health for work performed as part of the current study. Anil K. Sood has received grants from the National Institutes of Health (CA109298 and CA209904) for work performed as part of the current study and has acted as a paid consultant for Merck and Kiyatec, is a shareholder in BioPath, and has received research funding from M‐Trap for work performed outside of the current study. Steve W. Cole has received grants from the National Institutes of Health for work performed as part of the current study.
Funding Information:
Supported in part by National Institutes of Health grants CA193249, CA140933, CA246540 (to Susan K. Lutgendorf), CA109298, CA209904, ACS Research Professor Award (to Anil K. Sood), AG017265 and AG043404 (to Steve W. Cole), and P30CA086862 (Principal Investigator: George Weiner). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Susan K. Lutgendorf has received grants from the National Institutes of Health for work performed as part of the current study. Frank Penedo has received grants from the National Institutes of Health for work performed as part of the current study. Michael J. Goodheart has received grants from the National Institutes of Health for work performed as part of the current study. Laila Dahmoush has received grants from the National Institutes of Health for work performed as part of the current study. Jesusa M. G. Arevalo has received grants from the National Institutes of Health for work performed as part of the current study. Premal H. Thaker has acted as a paid consultant or speaker for Stryker, Iovance Biotherapeutics, AbbVie/Stemcentrx, Clovis Oncology, Unleash Immunolytics, and Celsion Corporation; has received research funding and personal fees from Merck and GlaxoSmithKline; has received personal fees from AstraZeneca; and is a Celsion shareholder. George M. Slavich has received grants from the National Institutes of Health for work performed as part of the current study. Anil K. Sood has received grants from the National Institutes of Health (CA109298 and CA209904) for work performed as part of the current study and has acted as a paid consultant for Merck and Kiyatec, is a shareholder in BioPath, and has received research funding from M-Trap for work performed outside of the current study. Steve W. Cole has received grants from the National Institutes of Health for work performed as part of the current study.
Publisher Copyright:
© 2020 American Cancer Society
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Background: Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. In patients with ovarian cancer, social isolation has been found to be related to decreased survival and multiple biomarkers supporting tumor progression. However, to the authors' knowledge, little is known regarding the relationship between social isolation and the molecular characteristics of ovarian tumors. Herein, the authors have used genome-wide transcriptional profiling to quantify associations between social isolation and epithelial-mesenchymal transition (EMT) polarization in ovarian tumors and transcriptome-driven, promoter-based bioinformatics analyses to identify gene regulatory pathways that may potentially underlie these changes. Methods: Tumor was sampled during primary surgical resection and immediately frozen in liquid nitrogen. After RNA extraction, microarray analysis of the transcriptome was performed and samples were analyzed to assess associations between EMT-related gene transcripts and social isolation (as indicated by a Social Provisions Scale Attachment subscale score <15). Convergent validation was provided by a promoter-based bioinformatic analysis of transcription factor activity. Results: Primary analyses of 99 women demonstrated a lower average expression of gene transcripts previously associated with epithelial differentiation in women with high social isolation (−0.143 ± 0.048 log2 mRNA abundance; P =.004), but no difference in mesenchymal differentiation as a function of social isolation (+0.007 ± 0.0064 log2 mRNA abundance; P =.900). Upregulated activity was shown for 3 of the 4 targeted EMT-related transcription factors, including GATA4 (P =.014); SMAD2, SMAD3, and/or SMAD4 (P <.001); and TWIST1 (P <.001). Analyses of SNAIL2/SLUG activity indicated a directional trend toward increased activity that did not reach statistical significance (P =.123). Conclusions: The findings of the current study demonstrated differential EMT polarization and EMT-related transcription factor activity according to social isolation, a known socioenvironmental risk factor. Lay Summary: Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. Herein, the authors examined the relationship between social isolation and the molecular characteristics of ovarian tumors. The authors investigated the epithelial-mesenchymal transition (EMT), a process whereby tumor cells lose epithelial characteristics and become more embryonic (mesenchymal), thereby enhancing invasiveness. Primary analyses demonstrated lower expression of genes previously associated with epithelial differentiation and increased activity of specific EMT-related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients. These findings extend the understanding of how socioenvironmental factors may modulate tumor growth.
AB - Background: Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. In patients with ovarian cancer, social isolation has been found to be related to decreased survival and multiple biomarkers supporting tumor progression. However, to the authors' knowledge, little is known regarding the relationship between social isolation and the molecular characteristics of ovarian tumors. Herein, the authors have used genome-wide transcriptional profiling to quantify associations between social isolation and epithelial-mesenchymal transition (EMT) polarization in ovarian tumors and transcriptome-driven, promoter-based bioinformatics analyses to identify gene regulatory pathways that may potentially underlie these changes. Methods: Tumor was sampled during primary surgical resection and immediately frozen in liquid nitrogen. After RNA extraction, microarray analysis of the transcriptome was performed and samples were analyzed to assess associations between EMT-related gene transcripts and social isolation (as indicated by a Social Provisions Scale Attachment subscale score <15). Convergent validation was provided by a promoter-based bioinformatic analysis of transcription factor activity. Results: Primary analyses of 99 women demonstrated a lower average expression of gene transcripts previously associated with epithelial differentiation in women with high social isolation (−0.143 ± 0.048 log2 mRNA abundance; P =.004), but no difference in mesenchymal differentiation as a function of social isolation (+0.007 ± 0.0064 log2 mRNA abundance; P =.900). Upregulated activity was shown for 3 of the 4 targeted EMT-related transcription factors, including GATA4 (P =.014); SMAD2, SMAD3, and/or SMAD4 (P <.001); and TWIST1 (P <.001). Analyses of SNAIL2/SLUG activity indicated a directional trend toward increased activity that did not reach statistical significance (P =.123). Conclusions: The findings of the current study demonstrated differential EMT polarization and EMT-related transcription factor activity according to social isolation, a known socioenvironmental risk factor. Lay Summary: Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. Herein, the authors examined the relationship between social isolation and the molecular characteristics of ovarian tumors. The authors investigated the epithelial-mesenchymal transition (EMT), a process whereby tumor cells lose epithelial characteristics and become more embryonic (mesenchymal), thereby enhancing invasiveness. Primary analyses demonstrated lower expression of genes previously associated with epithelial differentiation and increased activity of specific EMT-related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients. These findings extend the understanding of how socioenvironmental factors may modulate tumor growth.
KW - biobehavioral
KW - epithelial-mesenchymal transition
KW - ovarian cancer
KW - social isolation
KW - transcriptome
KW - treatment resistance
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U2 - 10.1002/cncr.33060
DO - 10.1002/cncr.33060
M3 - Article
C2 - 32691853
AN - SCOPUS:85088240174
SN - 0008-543X
VL - 126
SP - 4407
EP - 4413
JO - Cancer
JF - Cancer
IS - 19
ER -