The role of smooth muscle derived factors in colorectal cancer metastasis

Colorectal cancer (CRC) is currently the second leading cause of death by cancer worldwide. In Norway, it is the most common cancer, affecting about 7% of the population. Early detection and optimized surgery have helped increase the survival of CRC patients, however, once metastasis (i.e. when cancer spreads to a different part of the body from where it started) occurs, survival rates plummet, making an essential need to identify new treatments that prevent and stop metastasis. The primary objective of the project is to provide insight into how CRC metastasis is regulated. CRC is originated in the intestinal epithelium, a layer of absorptive cells surrounded by muscular tissue (smooth muscle). We already know that cancer cells do not work alone; the environment in which they grow will determine their ability to expand and to become metastatic. Many different cell types of this environment are able to regulate cancer cell activity, and in this project, we aim to study the role of a specific understudied environmental partner; the smooth muscle. My previous work has demonstrated that the smooth muscle produces molecules that are able to modify the behavior of this epithelium, affecting even tumor formation. I will use state-of-the-art techniques to identify the factors produced by this smooth muscle and involved in the regulation of metastasis, as well as to find possible drugs that inhibit this process.

Colorectal cancer (CRC) is currently the second leading cause of cancer deaths worldwide. In Norway, it is the most common cancer, affecting about 7% of the population. Although the mortality rate of CRC patients has reduced in recent years, this is primarily due to earlier detection and optimized surgery rather than novel therapeutics. Thus, there is still an essential and urgent need for the identification of new therapeutic targets, in particular after tumor metastasis, where treatment options are very limited. In addition to cancer cells, tumors include associated cells that modify the state of the tumor by secreting soluble factors and changing the extracellular microenvironment. In CRC, tumors are originated in the intestinal epithelium, a layer of cells surrounded by muscle cells named smooth-muscle. Based on my previous research, I propose that in CRC tumors, smooth muscle cells could act as a tumor-associated cell, generating soluble factors able to regulate CRC metastasis. In this proposal, I aim to (i) identify the specific factors produced by smooth muscle cells, (ii) uncover how these factors make cancer cells metastatic-like using state-of-the-art intestinal organoids and in vivo tumor models in mice, and (iii) perform a drug screen aimed to identify metastasis inhibitors. Ultimately, the identification of new mechanisms of control of CRC metastasis will hopefully help in the design of new avenues for CRC treatment.