Final Report Summary - STARLIN (Cell migration in gut homeostasis and cancer invasion - role of microenvironment)
The entire intestinal epithelium is renewed every week due to cell division in the crypts coupled with cell migration towards the villi and loss of cells by apoptosis at the tip of villi. However, the mechanism responsible for the migration of intestinal cells remains largely unknown. Using ex vivo gut slice cultures, we found that in the crypts, epithelial cells move passively as a consequence of the pushing force generated by dividing cells. However, along the villi, cells move actively using actomyosin-rich basal cellular protrusions (Krndija et al in submission).
Uncoupling cell proliferation from apoptosis and possibly from cell migration can lead to pathologies such as cancer. In carcinoma in situ, the basement membrane (BM) represents a physical barrier that prevents spreading of the primary tumor to adjacent tissues. It is believed that cancer cells perforate BM, but stromal cells such as carcinoma-associated fibroblasts (CAFs) also secrete matrix proteinases. Thus, the question is who is invading whom - do cancer cells invade the stroma or is the stroma invading tumor cells? We found that in the presence of primary colon CAFs, cancer cells invade the basement membrane in a protease-independent manner. Using live imaging and atomic force microscopy we found that CAFs use mechanical forces to remodel the basement membrane, leading to the formation of gaps through which cancer cells can migrate (Glentis et al, 2017). Once the BM becomes compromised, cancer cells migrate through the stroma towards the blood vessels, allowing dissemination of the tumor and formation of metastasis. Besides secreting growth factors that can stimulate invasive migration of cancer cells, CAFs can also actively excavate passageways in the ECM and lead cancer cell invasion. We found that CAFs assemble fibronectin fibrils via integrin β3 that triggered invasion of cancer cells through the stroma (Atieh et al, 2017).
Uncoupling cell proliferation from apoptosis and possibly from cell migration can lead to pathologies such as cancer. In carcinoma in situ, the basement membrane (BM) represents a physical barrier that prevents spreading of the primary tumor to adjacent tissues. It is believed that cancer cells perforate BM, but stromal cells such as carcinoma-associated fibroblasts (CAFs) also secrete matrix proteinases. Thus, the question is who is invading whom - do cancer cells invade the stroma or is the stroma invading tumor cells? We found that in the presence of primary colon CAFs, cancer cells invade the basement membrane in a protease-independent manner. Using live imaging and atomic force microscopy we found that CAFs use mechanical forces to remodel the basement membrane, leading to the formation of gaps through which cancer cells can migrate (Glentis et al, 2017). Once the BM becomes compromised, cancer cells migrate through the stroma towards the blood vessels, allowing dissemination of the tumor and formation of metastasis. Besides secreting growth factors that can stimulate invasive migration of cancer cells, CAFs can also actively excavate passageways in the ECM and lead cancer cell invasion. We found that CAFs assemble fibronectin fibrils via integrin β3 that triggered invasion of cancer cells through the stroma (Atieh et al, 2017).