Charlotte Rolny's Group

Deciphering underlying mechanisms that control immunosuppressive and angiogenic macrophage phenotypes.

Accumulation of Tumor-Associated Macrophages (TAMs) associate with tumor progression and poor survival in most cancers including those of the breast1. TAMs are plastic cells that exhibit a spectrum of states spanning from an anti-tumor/immunoactivating (sometimes referred to as a M1-like) to a pro-tumor/immunosuppressive (sometimes referred to as a M2-like) phenotype. We proposed already in 2011 that TAMs of an anti-tumoral phenotype located in the vicinity of tumor vessels (perivascular TAMs) promote vessel normalization that hampers metastatic dissemination. These TAMs further stimulate activation of cytotoxic T cells that kills tumor cells, resulting in suppression of tumor growth. Importantly pro-tumoral perivascular TAMs and low accumulation of T cells in malign Breast Cancer (BC) tumors correlate to poor prognosis and increased risk of distant. Our research aims to unravel the underlying mechanisms whereby TAMs pro-tumoral functions are regulated. In this respect, we recently illuminated a new mechanism whereby selective modification of mRNA translation regulate TAM immunosuppressive functions. Further mechanistic studies revealed that these functions were controlled by the eukaryotic initiation factor (eIF) 4E and the mitogen-activated protein kinase (MAPK) interacting protein kinase (MNK) signaling pathways, that regulate which mRNAs that will be translated. Additionally, preliminary data indicate that MNKs are involved in controlling the pro-metastatic functions of perivascular TAM. Our overall aim is to understand how TAM immunosuppressive and pro-metastatic functions are regulated and if these TAMs can be used as predictive and prognostic tools for breast cancer and sarcoma.

 

Immunofluorescence staining of CD34+ vessels and CD68+ TAMs in ER+ BC (left pictogram) and of CD31+ tumor vessels and F4/80+ TAMs  in mammary tumors (right pictogram).

Current projects

  • Deciphering underlying mechanisms that regulates TAMs pro-metastatic functions  that controls vessel perfusion and metastatic dissemination.
  • Metabolic pathways that regulate TAM phenotypes.
  • Exploiting TAM subtypes for chemotherapy efficacy.
  • Tyrosine kinase signaling pathways that are involved in regulating expansion of immunosuppressive TAMs
  • TAMs as predictive and prognostic tools in breast cancer and sarcoma

Group members

Charlotte Rolny, Associate Professor, Group leader
Yangxun Pan PhD student
Dongmei Tong, Post-doctoral fellow
Sabrina Ferreira, Post-doctoral fellow
Margarita Bartish, affiliated

Funding

  • Swedish Research Council (VR)
  • Swedish Cancer Society
  • Cancer Society in Stockholm
  • Karolinska Institutet Funds
  • Tornspiran

Selected publications

MNK2 governs the macrophage antiinflammatory phenotype.
Bartish M, Tong D, Pan Y, Wallerius M, Liu H, Ristau J, et al
Proc Natl Acad Sci U S A 2020 Nov;117(44):27556-27565

High density of stroma-localized CD11c-positive macrophages is associated with longer overall survival in high-grade serous ovarian cancer.
Corvigno S, Mezheyeuski A, De La Fuente LM, Westbom-Fremer S, Carlson JW, Fernebro J, et al
Gynecol Oncol 2020 Oct;():

STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer.
Zerdes I, Wallerius M, Sifakis EG, Wallmann T, Betts S, Bartish M, et al
Cancers (Basel) 2019 Oct;11(10):

Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity.
Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, et al
iScience 2018 Nov;9():71-83

Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis.
Georgoudaki AM, Prokopec KE, Boura VF, Hellqvist E, Sohn S, Östling J, et al
Cell Rep 2016 05;15(9):2000-11

Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages.
Wallerius M, Wallmann T, Bartish M, Östling J, Mezheyeuski A, Tobin NP, et al
Cancer Res. 2016 06;76(11):3166-78

Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.
Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, et al
Science 2015 Mar;347(6226):1138-42

Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models.
Casazza A, Fu X, Johansson I, Capparuccia L, Andersson F, Giustacchini A, et al
Arterioscler Thromb Vasc Biol 2011 Apr;31(4):741-9

HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, et al
Cancer Cell 2011 Jan;19(1):31-44