Exploring tumor heterogeneity

Cancer is a heterogeneous disease, which is reflected both on the cellular and the population level. Advances in detection, diagnosis, and treatment of malignancies have increased survival time of cancer patients; yet, the heterogeneity observed within and between tumors complicates accurate prognostication and interferes with efficacy of treatment. Heterogeneity is a global concept, mirrored for instance by the fact that the two vastly distinct cancer types discussed in this thesis - glioblastoma and colorectal cancer - are each characterized by high levels of tumor heterogeneity. Tumors have been recognized as ‘abnormal organs’ because transformed cells within one tumor exist in distinct states and intricately crosstalk with non-transformed cells in the tumor microenvironment. The term intra-tumor heterogeneity conceptualizes this notion. Inter-tumor heterogeneity refers to the fact that no tumor is like any other, which is illustrated most obviously by the comparison of tumors arising in different organs. The cells targeted for transformation, the transformation-initiating event, the environmental composition, and many more factors differ between neoplasms arising for instance in the brain (glioblastomas) and in the colon. Moreover, these parameters can also differ between tumors arising in the same organ, leading to the formation of distinct subtypes within a given type of cancer. Drivers of intra- and inter-tumor heterogeneity are the main focus of this thesis. Even though tumor heterogeneity presents a major challenge for the clinical management of individual patients, its presence allows the design of tailored therapeutic approaches and therefore exploring tumor heterogeneity holds promise for the design of personalized treatment strategies