Marta Torroella-Kouri, Ph.D.
Research Assistant Professor of Microbiology & Immunology
Description of Research
Tumors modify macrophages: Tumor progression is associated with immune suppression, mainly locally in the tumor microenvironment, although in later stages of tumor progression it may be also systemic. The interplay between a tumor and its host’s immune system and the mechanisms displayed by the tumor that eventually control and overcome the otherwise healthy host’s immune response are part of Dr. Torroella's research. She is particularly interested in the role of the innate immune response in cancer, especially in the activity of monocytes/macrophages, as targets of tumor-induced immune suppression. Tumors “educate” macrophages at the tumor microenvironment and make them contribute to cancer progression; the presence of macrophages in the tumor microenvironment is a recognized sign of poor tumor prognosis. Working with a mouse mammary tumor model, Dr. Torroella's group has shown a profound and progressive decrease in the differentiation, inflammatory functions and survival of blood monocytes, peripheral tissue macrophages and tumor-associated macrophages, demonstrating the existence of local and also systemic immune suppression in tumor hosts. They showed that mixtures of pro-inflammatory (M1) and immunosuppressed (M2) monocytes and macrophages coexist in the blood, peripheral tissues and tumor microenvironment of tumor bearers. Identifying the molecular mechanisms governing macrophage functions in the context of cancer and understanding how the host's immune response is modulated by tumor factors are important issues in designing cancer treatments.
Obesity, inflammation, breast adipose tissue and breast cancer: Dr. Torroella also studies the role of tumor-promoting macrophages in the context of obesity. Obesity, an epidemic and a new disease in our country, is associated with a systemic low-grade inflammation and also with local inflammation of visceral adipose tissues (AT). Obesity increases the risk of many cancers; it augments the risk of breast cancer (BC) in postmenopausal women and is associated with poor BC prognosis regardless the menopause status. Large numbers of pro-inflammatory (M1) macrophages occur in visceral obese AT, whereas anti-inflammatory (M2) macrophages exist in lean AT. AT is a significant component of the breast gland, yet its role in BC development in obese/overweight females has been poorly studied. Dr. Torroella is particularly interested in elucidating the role that breast AT – as a critical component of the BC microenvironment- may play in BC development in obese females. She investigates the crosstalk between adipocytes, tumor cells and macrophages in the BC microenvironment. She hypothesizes that adipokines (such as leptin, main regulator of satiety but also essential in BC), chemokines (such as CCL2), saturated fatty acids (ligands of TLR4) and estrogen, produced by adipocytes and tumor cells in the BC microenvironment, participate in macrophage recruitment and activation and are relevant to BC development. Using a diet-induced obese mouse model of BC, Dr. Torroella examined whether BC progression in obese females can be controlled by regulating macrophage recruitment and modulation of their inflammatory functions using two novel molecules: a leptin-receptor antagonist and a integrin Mac-1 agonist. Moreover, Dr. Torroella is initiating studies in obese and overweight BC patients. Her group has shown that there is a highly significant association in BC between tumor-associated and fat-associated macrophages (crown-like structures, CLS) with ethnicity. They discovered that African American and Latina women, with more aggressive BC and also with higher prevalence of obesity, exhibit higher breast AT inflammation than Caucasian patients. Her laboratory is currently elucidating the features exhibited by tumor-associated and fat-associated macrophages from obese tumor bearer females, and whether and how they ma
- Identified several molecular mechanisms (alterations in NFκB, C/EBP, STAT1, STAT3, IRAK-1, etc) by which macrophages residing in different locations in tumor hosts (peripheral and mammary tumor-associated macrophages), as well as their precursor blood monocytes, are targeted by tumors to impair their inflammatory functions, differentiation and viability. She found that tumor-associated macrophages in mice and human breast tumors consist of mixtures of pro and anti-inflammatory macrophages. She has shown for the first time that increased myelopoiesis in tumor hosts is also associated with increased macrophage apoptosis.
- Demonstrated an increased gradient of macrophage impairment and diversity in the corresponding mechanisms with the proximity to the tumor microenvironment (blood monocytes/peritoneal macrophages/ tumor-associated macrophages).
- Showed that crosstalk of adipocytes from obese murine mammary adipose tissue with mammary tumor cells and macrophages contributes to monocyte recruitment and to the expression of leptin, fatty acids, estrogen, CCL2 and several other chemokines, cytokines and growth factors (among them IL-6 and IP-10 (CXCL10) that are tumor-promoting and chemotactic to macrophages and to other inflammatory cells in the tumor microenvironment.
- Provided the first comprehensive study of the pleiotropic effects of leptin on macrophages: leptin regulates macrophage M1/M2 activation, modulates their differentiation and expression of important tumor-promoting signaling pathways in macrophages, such as NFκB, STAT3, Notch 3 and IRAK1; leptin also down regulates its receptor expression in macrophages.
- Demonstrated that in obese mice – but not in lean mice - the breast adipose tissue is inflamed, containing more macrophages (which are a mixture of pro- and anti-inflammatory), crown like structures and hypertrophic adipocytes. Studies also revealed that the proximity with tumor cells increases the inflammation in breast adipose tissue.
- Revealed that integrin Mac-1 activation through a novel compound used to treat obese tumor-bearing mice (leukadherin LA-1) reduces tumor progression by itself and in synergism with taxol through a reduction in tumor angiogenesis. Also, that this novel agonistic compound regulates Mac-1 expression and M1/M2 activation profiles in macrophages.
- Demonstrated for the first time a highly significant association between human breast adipose tissue inflammation and ethnicity in breast cancer, with African-American and Latina breast cancer patients showing higher inflammation in their breast microenvironments.
Selected Cancer-Related Publications
- Torroella-Kouri M, Silvera R, Rodriguez D, Caso R, Shatry A, Opiela S, Ilkovitch D, Schwendener RA, Iragavarapu-Charyulu V, Cardentey Y, Strbo N, Lopez DM. Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69:4800-9, 2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):