The Cittelly laboratory studies the mechanisms that allow breast cancer cells to metastasize to the brain, with long-term goal of identifying alternative treatment options for women with this -often terminal- diagnosis. Different from lung and bone metastases (which are common sites of breast cancer metastases), brain metastases develop in a unique organ comprised by a very specialized groups of cells that control brain function in a tightly regulated manner. We are interested in defining the mechanisms by which glial cells (reactive astrocytes and microglia) play pro and anti-metastatic roles during brain colonization, defining how hormones alter the neuro inflammatory milieu through metastatic colonization, and how the brain niche contributes to failure of standard of care for brain metastasis (i.e Radiation, targeted therapies).
Young women with breast cancer have increased risk of developing brain metastases independent on the primary tumor subtype. We have found evidence suggesting that ovarian hormones, particularly estradiol, promotes brain metastatic colonization and progression by acting on estrogen-responsive cells within the brain niche. We have identified at least two of these mechanisms (upregulation of BDNF and EGF in astrocytes, which in turn activate TRKB and EGFR in cancer cells), and continue to define the downstream mechanisms by which EGFR and TrkB activation promote migration and invasion of cancer cells. We are also defining whether targeting these pathways (which are FDA-approved and can cross the BBB) would be useful for preventing or treating brain metastases.
In collaboration with breast oncologists and neurosurgeons at University of Colorado AMC, we have developed xenograft models derived from breast cancer brain metastases from all breast cancer subtypes. We have engineered a protocol for manipulation of gene expression in these PDXs, including expression of optical labels for in vivo tracking, which allow us to model spontaneous and experimental metastasis of these PDXs in vivo. We are combining these with our spontaneous and experimental metastasis models in transgenic mice, to mechanistically evaluate the interactions between cancer cells and specific cells within the brain microenvironment during metastatic progression.
The majority of patients with brain metastasis are treated with radiation (stereotactic radiosurgery-SRS) as part of their standard of care. However, radiation induced toxicity (necrosis and edema) has emerged as critical side effect, particularly for patients receiving certain combinations of targeted therapies for their tumors. We have identified dysregulation of water-channels APQ4 in astrocytes, as one mediator of cytotoxic edema in the brain following SRS. Current projects further define how radiation alone or in combination with standard of care for breast cancer influence the development of radiation-necrosis and edema.
1. Sartorius CA, Hanna CP, Gril B, Cruz H, Kabos P, Serkova NJ, Huber KM, Schedin TB, Borges VF, Steeg PS, Cittelly DM. Estrogen promotes the brain metastatic colonization of triple negative breast cancer via an astrocyte-mediated paracrine mechanism. Oncogene. 2016; 35(22):2881-92. PMID: 26411365
2. Hanna CT, Kwok L, Finlay-Schultz J, Sartorius CA, Cittelly DM. Labeling of breast cancer patient-derived xenografts with traceable reporters for tumor growth and metastasis studies. 2016. Jove. 2016; (117). PMID: 27929464.
3. Contreras-Zárate MJ, Ormond DR, Gillen AE, Hanna C, Day NL, Serkova NJ, Jacobsen BM, Edgerton SM, Thor AD, Borges VF, Lillehei KO, Graner MW, Kabos P, Cittelly DM. Development of Novel Patient-Derived Xenografts from breast cancer Brain metastases. Front Oncol. 2017 Nov 2; 7:252. doi: 10.3389 /fonc.2017.00252. eCollection 2017. PMCID: PMC5673842
4. Contreras-Zárate MJ, Day NL, Ormond DR, Borges VF, Tobet S, Gril B, Steeg P, Cittelly DM. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene. 2019 https://doi.org/10.1038/s41388-019-0756
5. Stumpf PK*, Cittelly DM*, Robin TP, Carlson JA, Sthr KA, Contreras-Zárate MJ, Lai S, Ormond DR, Rusthoven CG, Gaspar LE, Rabinovithc R, Kavanagh B, Liu A, Diamond JR, Kabos PK, Fisher CM. Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of Aquaporin-4. Clin Cancer Res. 2019 Apr 2. pii: clincanres.2851.2018. doi: 10.1158/1078-0432.CCR-18-2851. *Co-first authors.
The Cittelly Lab is looking for creative thinkers, innovators, and problem solvers. People who can see the “big picture” while being meticulous about details. People who makes good use of their time and lab resources and is committed to the success of the lab as it is their own. People who are respectful, professional and enjoy working in the lab and with others. Please contact Diana.Cittelly@ucdenver.edu for more info.