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Targeting the Hippo pathway for cancer therapy: Discovering endogenous tumor suppressor mechanisms

Cancer is a leading cause of death worldwide, currently responsible for about 10 million deaths every year. Unfortunately, despite extensive research within this field, how cancer originates is not completely understood. The predominant theory about the genesis of cancer suggests that it arise when cells accumulate a certain amount of driver mutations. These mutations reprogram normal cells into cancerous cells, through progressive changes that result in cells more capable of surviving, evading the immune system, and aberrantly growing and dividing. However, recent evidence indicates that mutations alone are not always sufficient to explain carcinogenesis, suggesting that mutagenesis cooperates with other mechanisms to trigger cancer. This thesis summarizes the research conducted during my PhD, whose overarching goal is to generate new fundamental knowledge about the processes that regulate carcinogenesis. Interestingly, we found that cell competition is one of these processes. Cell competition is a mechanism by which adjacent cells with different cellular fitness compete for survival. Ultimately, the fitter cell (winner) eliminates and replaces the less fit cell (loser). The role of cell competition and how it influences carcinogenesis was studied in two parallel projects, using the mouse liver as a model organism.

 

In the first study (Chapter 3), we investigated how early events in metabolic dysfunction-associated steatohepatitis (MASH) affect hepatocytes harboring cancer-driver mutations. We found that early MASH did not hinder the malignant reprogramming of oncogene-expressing hepatocytes but suppressed their clonal expansion and led to their elimination. This elimination was caused by activation of a cell competition program driven by the Hippo pathway effector YAP. These findings suggest that, in mice, early MASH induces YAP-driven cell competition and activates a tumor suppressive program, which eliminates cells harboring driver-mutations and prevents liver cancer. 

 

Similarly, in our second study (Chapter 4), we found that mutations in oncogenes (Kras) or in tumor suppressor genes (Pten) can drive clonal expansion, when they occur in few hepatocytes, but not when activated in the entire liver. In addition, KRAS activation or Pten deletion in the liver tissue inhibited the development of liver cancer, through eliminating cells harboring additional mutations. This evidence suggests that, similar to YAP activation in MASH livers, KRAS activation and Pten deletion dive cell competition programs which can inhibit tumor development.

 

Collectively, these results highlight the need for a competitive environment for carcinogenesis. In the liver, when all cells harbor the same mutation, just like when none of them do, there are no differences in cellular fitness. The lack of fitness differences, thus, prevents the oncogene-driven malignant transformation. Moreover, we show how mutations in YAP, KRAS or Pten can elevate cell fitness, and therefore, tumor cells harboring these mutations (winner) can outcompete wild-type parenchyma (loser). Inducing these mutations in the liver parenchyma is sufficient to trigger the opposite situation; cancer cells (loser) are eliminated by liver parenchyma (winner). Overall, the research summarized in this thesis offers compelling proof of concept and underscores an important role of cell competition in cancer development. 

 

Date:29 Oct 2018 →  1 Mar 2024
Keywords:Hippo pathway, YAP/TAZ, hepatocellular carcinoma, cholangiocarcinoma, mouse models for liver cancer, tumorassociated vasculature, tumor elimination
Disciplines:Cell growth and development, Epigenetics, Cancer biology, Cancer therapy, Hepatology
Project type:PhD project