The Tumour Microenvironment
Tumours are not just made of tumour cells. Tumours are surrounded by a variety of non-cancerous cells called stromal cells that include fibroblasts, immune cells, blood vessels and a dense extracellular matrix, which form what is known as the tumour stroma or the tumour microenvironment. In some tumours, the stroma can represent up to 80% of the tumour mass and is not a simple bystander. In fact, the tumour microenvironment can support tumour initiation, progression, metastasis and drug resistance. The stromal cells co-exist, co-evolve and interact with cancer cells in tumours.
How tumours become resistant to therapies? How tumours evade the immune system? And how tumours metastasize to other organs are vital questions that remain to be addressed. Drug resistance, metastasis and the immune response against cancer are all influenced by the complex tumour microenvironment. The overall goal of our research is to understand how cancer cells interact with the stromal cells and how these tumour-stroma interactions affect drug resistance, tumour progression/metastasis and the immune response to tumours, with the aim to find more effective therapies for aggressive cancers such as pancreatic cancer and metastatic breast cancer.
To address these important questions we are using a variety of cutting-edge and innovative technologies that we have established in our lab, including flow & mass cytometry, fluorescent multispectral tissue imaging, proteomics with primary tumours, bioinformatics, 3D in vitro tumour models, patient samples, pre-clinical models and in vivo imaging.
Our work bridges basic/discovery research with clinical practice.
Our ultimate goal is to find better treatments for cancer patients.
We are happy to share our optimised experimental protocols to help advance scientific knowledge. Contact us!
– Dr Ainhoa Mielgo
Tumour-stroma interactions play a key role in cancer progression, metastasis and drug resistance.
Frequently Asked Questions
What is a macrophage?
A macrophage is a specialised type of immune cell which primary function is to engulf any foreign substance (i.e. pathogens, cancer cells) in a process called phagocytosis.
Macrophages are found in all tissues. Macrophages can be tissue resident or can arise from circulating monocytes from blood vessels and differentiate into macrophages in the tissue. Besides phagocytosis, macrophages also stimulate the recruitment and activation of another type of immune cells called lymphocytes, and support wound healing and tissue repair. There are different subsets of macrophages that exert distinct and even sometime opposite functions. M1-like macrophages promote inflammation and activation of the immune system, while M2-like macrophages support tissue repair and suppress the immune system.
What is the role of macrophages in cancer?
Macrophages are one of the most abundant cell types in the tumour microenvironment. Macrophages are among the first immune cells to infiltrate tumours. Cancer is associated with inflammation which results in the recruitment of circulating blood monocytes that give rise to TAMs (Tumour associated macrophages).
TAMs can secrete growth factors and enzymes that support tumour initiation, progression and metastasis. However, TAMs can also kill tumour cells. Hence, a better understanding of the pro-tumorigenic and anti-tumorigenic functions of TAMs could lead to the development of more effective anti-cancer therapies.
What is a fibroblast?
A fibroblast is a type of cell that is responsible for making the collagen and extracellular matrix required to maintain the structural integrity of all tissues in our body. Fibroblasts play an important role in wound healing. Following tissue injury, fibroblasts migrate to the site of damage, where they deposit new collagen and facilitate the healing process.
What is the role of fibroblasts in cancer?
Tumours are like wounds that do not heal. In fact, cells that are involved in wound healing such as fibroblasts and macrophages play also an important role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression and represent a promising target for cancer therapies. Therefore, their structural and functional contributions to cancer are being intensively investigated.
What is the function of the pancreas?
The pancreas is a digestive and endocrine organ in the abdominal cavity behind the stomach. The pancreas secretes digestive enzymes that assist the digestion and absorption of nutrients. The pancreas also secretes essential hormones, including insulin and glucagon that regulate the blood sugar (glucose) levels in our body
- Gaia Bellomo, Carolyn Rainer, Valeria Quaranta, Yuliana Astuti, Meirion Raymant, Elzbieta Boyd, Ruth Stafferton, Fiona Campbell, Dean E Hammond, Jennifer P Morton, Daniel Palmer, Dale Vimalachandran,Robert Jones, Ainhoa Mielgo & Michael C Schmid. Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut, DOI: 1136/gutjnl-2021-325272 (2022).
- Lucy Ireland, Teifion Luckett, Michael C Schmid, Ainhoa Mielgo
Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis. Frontiers in Immunology Feb 2020, doi: 10.3389/fimmu.2020.00297. eCollection (2020)
- Patrick Freeman and Ainhoa Mielgo. Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities. Cancers, doi: 10.3390/cancers12092687 (2020)
- Ainhoa Mielgo and Michael C. Liver Tropism in Cancer: The Hepatic Metastatic Niche. Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a037259 (2020).
- Lucy Ireland and Ainhoa Mielgo. Macrophages and Fibroblasts, Key Players in Cancer Chemoresistance. Frontiers in Cell & Dev. Biology, doi: 10.3389/fcell.2018.00131 (2018).
- Carlos Figueiredo, Ricardo Azevedo, Sasha Mousdell, Pedro Resende-Lara, Lucy Ireland, Almudena Santos, Natalia Girola, Rodrigo Cunha, Michael Schmid, Luciano Polonelli, Luiz R Travassos, Ainhoa Mielgo. Blockade of MIF-CD74 signalling on macrophages and dendritic cells restores the anti-tumour immune response against metastatic melanoma. Frontiers in Immunology, 2018, https://doi.org/10.3389/fimmu.2018.01132.
- Ireland L, Santos A, Campbell F, Figueiredo C, Hammond D, Ellies L, Weyer-Czernilofsky U, Bogenrieder T, Schmid M, Mielgo A. Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer. Oncogene, 2018, 37(15):2022-2036.
- Valeria Quaranta, Carolyn Rainer, Sebastian R Nielsen, Meirion Raymant, Muhammad S Ahmed, Dannielle Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel Palmer, David Tuveson, Ainhoa Mielgo, Michael Schmid. Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. Cancer Research, 2018, doi: 10.1158/0008-5472.CAN-17-3876.
- Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, Weyer-Czernilofsky U, Engle DD, Perez-Mancera P, Coupland SE, Taktak AF, Bogenrieder T, Tuveson DA, Campbell F, Schmid MC, Mielgo A. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Research, 2016, 1;76(23):6851-6863.
- Sebastian Nielsen, Valeria Quaranta, Andrea Linford, Perpetua Emeagi, Carolyn Rainer, Almudena Santos, Lucy Ireland, Takao Sakai, Keiko Sakai, Yong-Sam Kim, Dannielle Engle, Fiona Campbell, Daniel Palmer, Jeong Heon Ko, David Tuveson, Emilio Hirsch, Ainhoa Mielgo, and Michael Schmid. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nature Cell Biology, 2016, 18(5):549-60.
- Sunil Advani, Maria Fernanda Camargo, Laetitia Seguin, Ainhoa Mielgo , Sudarshan Anand , Angel Hicks , Joseph Aguilera, Aleksandra Franovic, Sara Weis and David Cheresh. Kinase-independent role for CRAF drives tumor radioresistance via CHK2. Nature Communications, 2015. Sep 3;6:8154.
- Laetitia Seguin, Shumei Kato, Aleksandra Franovic, M. Fernanda Camargo, Jacqueline Lesperance, Kathryn C. Elliott, Mayra Yebra, Ainhoa Mielgo, Andrew M. Lowy, Hatim Husain, Tina Cascone, Lixia Diao, Jing Wang, Ignacio I. Wistuba, John V. Heymach, Scott M. Lippman, Jay S. Desgrosellier, Sudarshan Anand, Sara M. Weis, David A. Cheresh. An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology. 2014. May;16(5):457-68.
- Ainhoa Mielgo, Laetitia Seguin, Miller Huang, Fernanda Camargo, Sudarshan Anand, Aleksandra Franovic, Sara Weis, Sunil Advani, Eric Murphy, David A. Cheresh. A MEK-independent role for CRAF in mitosis and tumor progression. Nature Medicine, Nov 2011 13; 17(12):1641-5.
- Ainhoa Mielgo, Vicente A. Torres, Kiran Clair and Dwayne G. Stupack. Paclitaxel promotes a caspase 8-mediated apoptosis via death effector domain association with microtubules. Oncogene, October 2009; 8;28(40):3551-62.
- Ainhoa Mielgo*, Wolf Wrasidlo*, Vicente A. Torres, Simone Barbero, Konstantin Stoletov, Takashi L. Suyama, Richard L. Klemke, William H. Gerwick, Dennis A. Carson and Dwayne G. Stupack. The marine lipopeptide somocystinamide A triggers apoptosis via caspase 8. Proc. Natl. Acad. Sci, 2008 February; 105(7): 2313-8. A.M and W.W contributed equally to this work.