Project titleEvaluating the role of p38 MAPK signaling pathway as a cross-link between colon tumor cells and fibroblasts

Colorectal cancer (CRC) is the third most diagnosed cancer in males, the second most diagnosed cancer in females, and one of the leading causes of cancer-related death in the world. CRC is characterized by the appearance of malignant polyps lining the inner surface of the colon or rectum. CRC arises from dysregulation of the cell cycle and activation of signaling pathways, such as p38 mitogen-activated protein kinase (MAPK) and transforming growth factor-beta 1 (TGF-β)/Smad. The role of these signaling pathways remain relatively unexplored in CRC. The aim of the current study is to evaluate the complex role of the p38 MAPK signaling pathway as a cross-link between colon tumor cells and fibroblasts. We predict that up-regulation of p38 MAPK expression in fibroblasts interacting with CRC cells mediates proliferation of CRC cells and results in a more pro-inflammatory phenotype of fibroblasts. Alternatively, if p38 MAPK signaling is inhibited, there would be a change in the fibroblast phenotype and its interaction with the CRC cells, thus indicating a cross-link between colon tumor cells and fibroblasts. Blocking of the p38 MAPK signaling pathway is predicted to also result in the downregulation of TGF-β and its receptors, as well as other chemokines indicative of a pro-inflammatory response. Expression of TGF-β receptors will be studied again to understand the role of TGF-β and downstream Smad proteins in the reprogramming of NFs following interactions with CRC cells. The secretion and expression of chemokines detected in potentially reprogrammed NFs may indicate a switch from an anti-inflammatory to a more pro-inflammatory signature. We also expect an increase in expression levels of Desmin given that Desmin expression correlates with the severity and differentiation of CRC, as well as phenotypic changes in NFs. By establishing an understanding of the multidimensional role of the p38 MAPK and TGF-β pathways, current studies will pave the way for future research by specifically blocking key pro-inflammatory players and evaluating mechanisms by which activated fibroblasts modulate the tumor microenvironment.

Primary contact nameAyah Salameh
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Students/participant(s) programs
  • Biological Sciences
Faculty advisor(s)
Advisor name Email Affiliation
Nesrine Affara CMUQ Professor
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  • Biological Sciences