Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma

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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.

Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 80%

Section: Psychosocial Demographic and Clinical Characteristicsmentioning

confidence: 99%

See 1 more Smart Citation

Epithelial‐mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation

Lutgendorf

Penedo

Goodheart

et al. 2020

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“…Because chronic stress can dampen the immune response to the influenza vaccine in older populations, an ongoing RCT is examining the effects of a remotely delivered CBSM intervention on stress and immunologic responses to the influenza vaccine in distressed older women who are receiving primary treatment for breast cancer . With evidence that stress processes contribute to immunologic and tumor cell biology changes and poorer clinical outcomes in skin, lung, ovarian, renal, hepatocellular, and hematologic cancers, it is imperative that trials evaluate the effects of SM interventions on stress, immunologic outcomes, and health outcomes in these and other cancers.…”

Section: Sm and The Immune Processes In Patients With Cancermentioning

confidence: 99%

“…61 Secondary analyses implicated the upregulation of genes associated with heightened sympathetic nervous system (SNS) activity and NF-κB family transcription factors. 61 Thus, during the perisurgical period of ovarian cancer, as in the case of breast cancer 56 and RCC, 57 greater adversity is associated with greater inflammatory signaling and processes favoring metastasis and poorer clinical outcomes.…”

Section: Chronic Stress-induced Exacerbation Of Chronic Inflammationmentioning

confidence: 99%

The impact of psychosocial stress and stress management on immune responses in patients with cancer

Antoni

Dhabhar

2019

202

197

The range of psychosocial stress factors/processes (eg, chronic stress, distress states, coping, social adversity) were reviewed as they relate to immune variables in cancer along with studies of psychosocial interventions on these stress processes and immune measures in cancer populations. The review includes molecular, cellular, and clinical research specifically examining the effects of stress processes and stress‐management interventions on immune variables (eg, cellular immune function, inflammation), which may or may not be changing directly in response to the cancer or its treatment. Basic psychoneuroimmunologic research on stress processes (using animal or cellular/tumor models) provides leads for investigating biobehavioral processes that may underlie the associations reported to date. The development of theoretically driven and empirically supported stress‐management interventions may provide important adjuncts to clinical cancer care going forward.

Biobehavioral factors predict an exosome biomarker of ovarian carcinoma disease progression

Lutgendorf

Thaker

Goodheart

et al. 2022

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Background Biobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors. Methods Exosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were analyzed by elastic net machine learning to identify a biomarker predicting rapid (≤6 months) versus more extended disease‐free intervals following initial treatment. Samples from a second subgroup of 24 patients were analyzed by mixed‐effects linear models to determine whether the progression‐predictive biomarker varied longitudinally as a function of biobehavioral risk factors (social isolation and depressive symptoms). Results An RNA‐based molecular signature was identified that discriminated between individuals who had disease progression in ≤6 months versus >6 months, independent of clinical variables (age, disease stage, and grade). In a second group of patients analyzed longitudinally, social isolation and depressive symptoms were associated with upregulated expression of the disease progression propensity biomarker, adjusting for covariates. Conclusion These data identified a novel exosome‐derived biomarker indicating propensity of ovarian cancer progression that is sensitive to biobehavioral variables. This derived biomarker may be potentially useful for risk assessment, intervention targeting, and treatment monitoring.