MSB LAB at IITI

Colorectal Cancer (CRC) is closely associated with chronic inflammation, which can contribute to cancer progression. Within the tumor microenvironment (TME), various immune cells play a crucial role in either promoting cancer aggressiveness or inhibiting cancer cell growth. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME and interact with cancer cells. CRC cells release soluble factors and exosomal miRNAs that reprogram macrophages, leading to increased cancer cell aggressiveness during colorectal cancer progression. The aim of our research is to comprehend the MAL-mediated signaling mechanism responsible for macrophage polarization induced by exosomes derived from CRC cells. This understanding will aid in the development of effective therapeutics for treating colorectal cancer.

Figure- Kinetics study of macrophages pro-/anti-inflammatory cytokines expression in colorectal cancer microenvironment.

We focus on a crucial inflammation-related adaptor of Toll-like receptors (TLR) called MyD88 adaptor-like (MAL). MAL contains a TIR domain required for mediating interactions with receptors on the membrane and with downstream signaling molecules. MAL represents a key mediator of TLR signaling in immune cells such as macrophages, where activation of TLR2 and TLR4 causes persistent inflammation in a MAL-dependent fashion. Following receptor-mediated detection of pathogenic ligands, MAL mediates various protein-protein interactions. The specific MAL interaction with its binding partner will determine the severity and type of inflammatory responses. Unraveling the protein-protein interactions of MAL would not only lead us to a greater understanding of the underlying signaling mechanisms that occur in the progression of various life-threatening chronic inflammatory conditions but would also guide us toward the development of important therapeutic strategies for disease treatment.

Figure - Molecular role of MAL in chronic inflammatory diseases. (A) Representation of the total network of TIRAP protein-protein interactions in macrophage inflammatory signaling. (B) Representation of the MAL-TIR domain and computational prediction of phosphorylation and S-nitrosylation (SNO) positions. (C) Schematic highlighting the interactions of MAL involved in disease progression. (D) MAL interactions under various stimulants.