A group of French and American scientists led by Dr. Géraldine Guasch at the Cancer Research Center in Marseille France (CRCM, INSERM) uncover how aggressive transition zone tumors grow and spread into organs, a process called ''metastasis''. The research, which identifies a key role for a protein in the metastatic process of certain cancers and thereby a potential avenue for future cancer treatments, has been published in eLife.
Deregulated TGF-β signaling: a hallmark of aggressive tumors occurring at transition zones
Many different types of cells make up the tissues and organs throughout our bodies. There are specific locations throughout the body where two very different types of cells are in contact with one another; these locations are called transition zones. Transition zones can be found between the cornea and the conjunctiva in the eye, at the junction between the oesophagus and the stomach, between the stomach and the duodenum, between the junction of the cervix and the vagina, in the ovary, and also between the anal canal and the rectum (anorectal), which has been used as a model of study in this work. The same transition zones present in humans are present in other species, thus enabling animal models to be used. Moreover, in humans and mice, these transition zones are prone to cancer formation. Many of these tumors are particularly aggressive, including those arising in the transition zone in the cervix, the junction between the esophagus and the stomach, and the anorectal transition zone. Aggressive tumors such as these frequently spread and form tumors in other organs such as the lung, a process called metastasis. Metastasis is the last parameter in the cancer staging system TNM (Tumor, Node, Metastasis) and synonym of poor prognosis for patients. To date, we still lack a clear understanding of what makes these transition zones prone to tumor formation or why the tumors that form there are so aggressive. Many of these aggressive transition zone tumors have abnormal regulation of a molecular pathway which cells use to communicate, the transforming growth factor beta (TGFβ) signaling pathway. Using mice deficient in TGFβ signaling that she had previously generated, which spontaneously develop aggressive transition zone tumors, Géraldine Guasch and her team found that only a small fraction of the tumor cells are responsible for tumor growth, and that these cells express genes that enhance their ability to migrate and invade.
Discovering the candidates for the metastatic exile
To proliferate and move, tumor cells in transition zones depend on ''super cells'' with stem cell properties, called cancer stem cells, that are uniquely able to divide and expand indefinitely in culture, to form new tumors and to induce metastasis when transplanted in recipient mice. First author of the study, Dr. Heather McCauley, a graduate student in the Guasch group at that time and now a postdoc at the Cincinnati Children's Hospital, has discovered the mechanism underlying the invasion process, by showing that the guanine exchange factor ELMO1 is responsible for the invasion and metastasis of the TGFβ deficient cancer stem cells.
''Our work establishes a clear correlation between the level of expression of ELMO1, responsible for the migration of the cancer cells and the level of aggressiveness of the tumor'' says McCauley. Indeed, decreasing the expression of ELMO1 in cancer stem cells dramatically affects cell migration in culture, changes the properties of the cancer stem cells in the tumor and impairs metastasis to the lung. Moreover, she identified ELMO1 as a novel target of TGFβ signaling and showed that restoration of the pathway results in complete block of ELMO1 in vivo. The team's work also showed that anorectal cancers in human patients with signs of compromised TGFβ signaling exhibit increased ELMO1 expression, which correlates with tumor stage.
"ELMO1 is a key factor in the exile of tumor cells and thus targeting ELMO1 may be a promising pathway for preventing metastasis from transition zone tumors'' concludes Guasch.
This research was supported by grants from the V Foundation, the Sidney Kimmel Foundation and in part from the Fondation ARC pour la recherche sur le cancer.
Article: De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFβ-deficient squamous cell carcinoma from transition zones, Heather A. McCauley, Véronique Chevrier, Daniel Birnbaum and Géraldine Guasch, eLife, doi: 10.7554/eLife.22914, published 21 February 2017.