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Endowed Professor of Cell Biology
Founding Director of the Cancer Dormancy and Tumor Microenvironment Institute
Director of the Gruss-Lipper Biophotonics Center
Co-Leader Tumor Microenvironment and Metastasis Program, AECC
Price Bldg., Room 220
Research Interest
Biosketch
Aguirre-Ghiso Lab
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CANCER DORMANCY: UNDERSTANDING THE BIOLOGY OF METASTASIS
The major challenge faced by physicians is the prevention and treatment of metastasis, the main reason for cancer mortality. Often, cancer patients presumed cured after primary tumor removal and therapy, can carry non-proliferating ‘dormant’ disseminated cancer cells (DCCs) for years before reactivating to form incurable metastasis. In addition, DCCs show resistance to standard treatments by reprogramming themselves in a niche-dependent manner. Our lab specifically focused on the dormant nature of minimal residual disease in cancer by understanding the biology of dormant DCCs and their reactivation, to target them and prevent relapse. We focus on identifying the mechanisms of microenvironmental cues and cross-talk with DCCs, epigenetic and immune regulation of DCCs, and developing therapeutic approaches to target DCCs clinically.
1. Mechanisms of early dissemination, dormancy and metastasis. We explored why in many patients metastasis remain dormant in the bone marrow. We found that the bone marrow contains high levels of TGFβ2, which induced dormancy via TGFβ-RI/RII/RIII complexes and p38 signaling. Using mouse genetics, we showed that a key source of TGFβ2 is the NG2+/Nestin+ mesenchymal stem cells (MSCs) that induce hematopoietic stem cell dormancy and self-renewal and also proved that these MSCs induce and maintain dormancy of breast cancer DCCs in the bone marrow. Analysis of the transcriptional and epigenetic mechanisms active in dormant DCCs pinpointed retinoic acid as a micro-environmental pro-dormancy cue. We found that the orphan nuclear receptor NR2F1, which regulates lineage commitment and is silenced in human tumors, is spontaneously upregulated in solitary dormant tumor cells. Retinoic acid induces TGFβ2, NR2F1 expression and dormancy of DCCs. We found that a transient treatment with low dose of 5-azacytidine, followed by all-trans retinoic acid, restored the NR2F1-driven program and long-term in vivo quiescence of previously malignant cells. Our work revealed markers that predict for longer metastasis-free periods in ER+ breast cancer patients. These signatures can be found in single DCCs from prostate cancer patients in clinical dormancy for up to 18 years and not in DCCs from patients with advanced disease.
• Bragado, P., et al.,(2013). Nat Cell Biol PMID 24161934
• Sosa, M.S., et al.,(2015). Nat Commun PMID 25636082
• Nobre et al., (2021) Nat Cancer NIHMSID1675122
• Fane et al., (2021) Preprint – Research Square doi: 10.21203/rs.3.rs-61165/v1
2. Early dissemination and early DCC dormancy. Our lab has discovered that dormant breast cancer DCCs and metastasis can originate very early during cancer evolution, disseminating during pre-malignant stages and aided by innate immune cells. We identified a mechanism for early dissemination whereby Her2 aberrantly activates a program similar to mammary ductal branching that spawns early DCCs (eDCCs) capable of forming metastasis after a dormancy phase. We also revealed how the HER2 oncogene activates through CCL2 signaling the recruitment of tissue resident macrophages that help eDCCs to enter circulation. Targeting these macrophages early in cancer evolution reduced metastasis late in cancer progression. Our focus is to understand how eDCCs found metastasis directly and/or through the preparation of eDCC-orchestrated pre-metastatic niches for later arriving DCCs to colonize target organs. We also aim to identify markers that might pinpoint early DCCs vs late DCCs and that may allow selectively targeting these cells.
• Harper, K, Sosa MS., et al., (2016) Nature. PMID 27974798
• Hosseini et al., (2016) Nature. PMID 27974799
• Linde and Casanova-Acebes et al., (2018) Nat Commun. PMID 29295986
• Nobre et al., (2021) Preprint – Research Square doi: 10.21203/rs.3.rs-145308/v1
3. The balance between mitogenic and stress signaling as a determinant of dormancy. We found that the ERK to p38 ratio was predictive of cancer cell dormancy or reactivation across different cancers, including HNSCC, breast and prostate. Our lab discovered that all cancer cells activate p38 upon dissemination but those that go on to metastasize from DCCs silence p38 signaling. We also found that p38 induced in dormant cells an unfolded protein response, upregulation of the chaperone BiP and activation of the ER kinase PERK. We also discovered that stress signaling activated by hypoxia in primary tumor microenvironments gives rise to a sub-population of dormant DCCs that evade therapy and may be the source of disease relapse and poor prognosis associated with hypoxia.
• Aguirre-Ghiso, J.A., et al., (2004). Cancer Res. PMID 15492254
• Schewe, D.M., and Aguirre-Ghiso, J.A. (2008). PNAS USA. PMID 18650380
• Adam, A.P. et al., (2009). Cancer Res. PMID 19584293
• Fluegen et al., (2017) Nat Cell Bio PMID 28114271
4. Adhesion, stress signaling and autophagy. We found that p38 is activated upon loss of integrin adhesion signaling leading to ERK1/2 inhibition and induction of the pro-apoptotic protein BimEL. This is key to induce anoikis, proper development of the mammary tree. We found that the HER2 oncogene inhibits p38 to accelerate cancer progression via anoikis resistance. We also discovered that proper adhesion signaling limits activation of the endoplasmic reticulum PERK, which limits mammary cancer initiation by blocking proliferation. We found that ErbB2 signaling is dependent on optimal activation of eIF2a signaling and that causing an imbalance in P-eIF2a levels killed ErbB2-overexpresing cells. We also showed that PERK-eIF2a-ATF4-CHOP activation in ECM-detached mammary epithelial cells induces autophagy and antioxidant responses for survival.
• Ranganathan et al., (2006 & 2008) Cancer Res. PMID 16452230, 18451152
• Schewe DM and Aguirre-Ghiso, JA (2009). Cancer Res.PMID19190324
• Avivar-Valderas, A., et al., (2011). Mol Cell Biol PMID 21709020
• Wen, H.C., et al.,(2011). Science Signaling. PMID21610252
• Avivar-Valderas A et al., (2013). Oncogene. PMID 23160380
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