The Brodt laboratory is studying the biology and clinical aspects of cancer metastasis with emphasis on the process of liver metastasis. Within this context, the following specific projects are being pursued:
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1)听The role of the IGF axis in liver metastasis: signaling and crosstalk with the microenvironment听
In this project, we investigate the role of the IGF axis in shaping the microenvironment of liver metastases using colon and lung carcinoma models. To this end, we utilize a combination of genetically-altered mouse models and gene-modified cancer cells.
Previous work established a link between IGF-IR signaling and type IV collagen production and demonstrated the essential role that extracellular matrix (ECM) collagen plays in liver metastasis (Burnier J. et al, Oncogene, 2011). In follow-up studies, we found that type IV collagen, through integrin signaling, can regulate gene transcription and increase听the expression of chemokines CCL5 and CCL7 in our cancer cells. Ongoing studies aim to elucidate the role of these chemokines in promoting liver metastasis.
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Recent representative publications:
Vaniotis G., Rayes, RF., Qi, S., Milette, S., Wang, S., Perrino, S., Nystr枚m, N., He Y., Lamarche-Vane N., and Brodt, P. Collagen IV-conveyed signals regulate chemokine production and promote liver metastasis. Oncogene 37(28):3790-3805, 2018.
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Source: Vaniotis G. et al听.听Collagen IV-conveyed signals听regulate chemokine production and promote liver metastasis. Oncogene 37(28):3790-3805, 2018.
Qi S, Perrino S, Miao X, Lamarche-Vane N,听Brodt P. The Chemokine CCL7 regulates Invadopodia maturation and MMP-9 mediated collagen degradation in liver-metastatic carcinoma cells.听Cancer Lett. 2020 Jul 28;483:98-113. doi: 10.1016/j.canlet.2020.03.018. Epub 2020 Mar 23.
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Source: Qi, S. et al. The Chemokine CCL7 regulates Invadopodia maturation and MMP-9 mediated collagen degradation in liver-metastatic carcinoma cells, Cancer Lett. 2020 Jul 28;483:98-113. doi: 10.1016/j.canlet.2020.03.018. Epub 2020 Mar 23.
In these publications, we show that by upregulating CCL7, type IV collagen could promote CCL7-mediated invadopodia genesis and thereby enhance the invasive/metastatic potential of cancer cells.
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In a second line of investigation, we used animals with an inducible, liver specific IGF-I deletion to examined the role of IGF signaling in shaping the stromal response and immune microenvironment of liver metastases. This work revealed that IGF-I plays a regulatory role in neutrophil polarization and in the activation of hepatic stellate cells in response to liver invasion by metastatic cancer cells.
Recent representative publications:
Fernandez, M.C., Rayes, R., Ham, B., Wang, N., Bourdeau, F., Milette, S., llemann, M., Bird, N., Majeed, A., Xu, J., Kisselova T and Brodt P. The type 1 insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells. Oncotarget. Oct 12; 8(32):52281-52293, 2016.
Rayes, RF., Milette, S., Fernandez, MC., Ham, B., Wang, N., Bourdeau, F., Perrino, S., Yakar , S., and Brodt, P. Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. Oncotarget. 9(21):15691-15704, 2018.
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2) The pro-metastatic microenvironment of the liver: role of inflammation听
In this project, we aim to dissect the crosstalk between metastatic cancer cells entering the liver and different cellular/molecular elements of the liver microenvironment. To this end, we are studying mice with genetically modified inflammatory responses such as TNF receptor deficiencies to dissect the role of different immune cell subsets in the process of metastasis. In this context, we recently reported on a sexual dimorphism in the control of the immune microenvironment of liver metastases by inflammatory signals. We showed that estrogen plays a major role in the induction of an immunosuppressive microenvironment in the liver and this promotes metastatic expansion.
Recent representative publication:
Milette S., Hashimoto M., P茅rrino S., Qi S., Chen M., Ham B., Wang N., Lowy AM., Piccirillo C., and Brodt P., 2019, Sexual dimorphism and the role of estrogen in the regulation of a pro-metastatic immune microenvironment in the liver. Nature Communications 10 (1), 5745- 61, 2019.
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Source: Milette S. et al. Sexual dimorphism and the role of estrogen in the regulation of a pro-metastatic immune microenvironment in the liver. Nature Communications 10 (1), 5745- 61, 2019.
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3) Developing an IGF Trap for prevention of cancer growth and metastasis
The objective of this project is to develop novel strategies for targeting the IGF axis, as means of blocking cancer growth and metastasis. We have used cell and gene therapy strategies for delivering a soluble IGF-I receptor in vivo into tumor-bearing mice and observed significant cancer growth inhibition. An IGF-TRAP was subsequently developed as an anti-cancer drug and recently further chemically modified to optimize biological and therapeutic activity (see also patents granted under 鈥淣ews鈥�).
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Recent听representative publication:
Vaniotis G., Moffett S., Sulea T., Wang N., Elahi SM., Lessard E., Baardsnes J., Perrino S., Durocher Y., Frystyk J., Massie B., and Brodt P. Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties. Scientific Reports. 8(1):17361-17374, 2018.
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Source:听 Vaniotis G. et al., Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties. Scientific Reports. 8(1):17361-17374, 2018.
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4) Developing strategies for treatment of听adult and听 Pediatric听 Glioblastoma
Glioblastoma multiforme (GBM) is an aggressive, infiltrative, and difficult to treat malignancy. It is characterized by intense and aberrant vascularization and is highly resistant to radiotherapy and chemotherapy. Despite intensive multimodal treatment strategies, the median survival of patients with GBM still stands at 12.1-14.6 months and only 3-5% of patients survive longer than 3 years. Thus, GBM represents an urgent unmet medical need. We are testing and optimizing delivery of the IGF-Trap for the treatment of adult and pediatric glioma tumors. This project, supported by the Ministry of Economy and Innovation of the Government of Quebec is a multi-national collaboration with biotechnology companies in Canada and Israel that have innovative proprietary technologies for transient and controlled opening of the blood brain barrier to allow delivery of biologicals to the brain for the treatment of brain malignancies (See more under 鈥淣ews鈥�)
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5)听 Combinatorial Immunotherapy for pancreatic ductal adenocarcinoma
Studies by our own group and others revealed that the IGF-axis plays a role in inducing an immunosuppressive and pro-metastatic microenvironment in the liver. Based on these findings, we are currently testing novel combinatorial immunotherapies in mouse models of pancreatic ductal adenocarcinoma by using immune checkpoint inhibitors together with the IGF-Trap.
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