The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development

Qureshi, Rehana; Picón-Ruiz, Manuel; Aurrekoetxea-Rodríguez, Iskander; Paiva, Vanessa Nunes de; D’Amico, Massimo; Yoon, Hyunho; Radhakrishnan, Ramya; Morata-Tarifa, Cynthia; Ince, Tan A.; Lippman, Marc E.; Thaller, Seth R.; Rodgers, Steven E.; Kesmodel, Susan B.; Vivanco, María dM; Slingerland, Joyce M.

doi:10.1016/j.cmet.2020.05.008

“…When paired with such dietinduced obesity (DIO), syngeneic tumor cell lines can be used to study cancer associated immune system changes during obesity. Increased tumor incidence and accelerated tumor growth have been demonstrated in multiple obese murine models (Incio et al, 2016a, Khasawneh et al, 2009, Tiwari et al, 2019, Cranford et al, 2019, Wang et al, 2019, Chung et al, 2020, Qureshi et al, 2020, Incio et al, 2016b. However, the immune cell compartment of the tumor microenvironment and its possible impact on obesity-induced tumors has not been systematically characterized at the single-cell level.…”

Section: Introductionmentioning

confidence: 99%

High-dimensional immunotyping of tumors grown in obese and non-obese mice

Wogsland

¹

,

Lien

²

,

Pedersen

³

et al. 2021

Disease Models &Amp; Mechanisms

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Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.

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“…Obese patients mostly have a global dysfunctional state mainly characterized by metabolic and immunologic alterations. This leads to an increased risk for developing various cancers among which BC, especially estrogen receptor (ER)-positive BC in the post-menopausal population [ 12 , 13 ]. Additionally, obesity has been shown to negatively impact the prognosis of BC patients [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Digital analysis of distant and cancer-associated mammary adipocytes

Isnaldi

¹

,

Richard

²

,

Schepper

³

et al. 2020

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Adipocytes and cancer-associated adipocytes (CAAs) are poorly investigated cells in the tumor microenvironment. Different image analysis software exist for identifying and measuring these cells using scanned hematoxylin and eosin (H&E)-stained slides. It is however unclear which one is the most appropriate for breast cancer (BC) samples. Here, we compared three software (AdipoCount, Adiposoft, and HALO®). HALO® outperformed the other methods with regard to adipocyte identification, (> 96% sensitivity and specificity). All software performed equally good with regard to area and diameter measurement (concordance correlation coefficients > 0.97 and > 0.96, respectively). We then analyzed a series of 10 BCE samples (n = 51 H&E slides) with HALO®. Distant adipocytes were defined >2 mm away from cancer cells or fibrotic region, whereas CAAs as the first three lines of adipocytes close to the invasive front. Intra-mammary heterogeneity was limited, implying that measuring a single region of ∼500 adipocytes provides a reliable estimation of the distribution of their size features. CAAs had smaller areas (median fold-change: 2.62) and diameters (median fold-change: 1.64) as compared to distant adipocytes in the same breast (both p = 0.002). The size of CAAs and distant adipocytes was associated with the body mass index (BMI) of the patient (area: rho = 0.89, p = 0.001; rho = 0.71, p = 0.027, diameter: rho = 0.87 p = 0.002; rho = 0.65 p = 0.049, respectively). To conclude, we demonstrate that quantifying adipocytes in BC sections is feasible by digital pathology using H&E sections, setting the basis for a standardized analysis of mammary adiposity in larger series of patients.

show abstract

“…When paired with such dietinduced obesity (DIO), syngeneic tumor cell lines can be used to study cancer associated immune system changes during obesity. Increased tumor incidence and accelerated tumor growth have been demonstrated in multiple obese murine models (Chung et al, 2020;Cranford et al, 2019;Incio et al, 2016a;Incio et al, 2016b;Khasawneh et al, 2009;Qureshi et al, 2020;Tiwari et al, 2019;Wang et al, 2019). However, the immune cell compartment of the tumor microenvironment and its possible impact on obesity-induced tumors has not been systematically characterized at the single-cell level.…”

Section: Introductionmentioning

confidence: 99%

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

Wogsland

¹

,

Lien

²

,

Pedersen

³

et al. 2020

Preprint

View full text Add to dashboard Cite

Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.

show abstract

The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development

Cited by 66 publications

References 88 publications

High-dimensional immunotyping of tumors grown in obese and non-obese mice

High-dimensional immunotyping of tumors grown in obese and non-obese mice

Digital analysis of distant and cancer-associated mammary adipocytes

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

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