Tumor Heterogeneity

In this infographic, we will explain what tumor heterogeneity means, explore its different types and describe its consequences for cancer treatment and therapy resistance. What is Heterogeneity describes the diversity of tumors – this can be within a tumor, within a patient or between different patients with the same tumor. Heterogeneity can be seen in Homogeneity describes how similar tumors are to each other. Heterogenous tumors have different biological, morphological, phenotypic and genotypic profiles. Most, but not all, cancerous tumors display some heterogeneity – it is one of the defining features of cancer. Tumors typically become more heterogenous over time as they accumulate mutations due to genetic instability and as they are treated with different therapies. genetics epigenetics protein production (such as single nucleotide variants or copy number changes), (DNA methylation and gene expression) (proteomics) Spatial heterogeneity The uneven distribution of diverse tumor cell populations. This can arise due to different influences from the tumor environment at different sites across a tumor, or between individual tumors at distant sites in the body. These influences include the interplay between cancer cells and surrounding tissue or the immune system, and outside factors such as the availability of blood supply, oxygen and nutrients. Temporal heterogeneity Variations in a single tumor over time due to natural progression or therapeutic interventions. Involves dynamic variation over time, for example, across cancer initiation, progression and metastasis. It often arises due to targeted treatments (which creates selection pressure) or genetic instability. Treatment & disease progression What are the different types of tumor heterogeneity? Tumor heterogeneity can be separated into several types: How does How can we heterogeneity affect cancer treatment? study heterogeneity? Heterogeneity can affect the discovery of biomarkers – molecules that indicate a particular characteristic – as well as the effectiveness of some treatments. Heterogeneity makes it difficult to design effective treatments or to eliminate all cancer cells. Drugs can target specific mutations identified in a tumor that drive its growth – usually the dominant clones. Therapies are a selection pressure – as the sensitive cells are eliminated, non-dominant clones expand and repopulate the tumor. Heterogeneity is one of the main barriers to successful therapies, and understanding its complexity is an ongoing challenge. Here are some examples of techniques by which we can characterize tumor heterogeneity: Multiregion sampling Liquid biopsy Spatial profiling Next-generation sequencing Tissue biopsies are the gold standard for clinical practice. Multiregion sampling involves gathering samples from multiple regions around a tumor, capturing a more accurate representation of spatial heterogeneity across a tumor, unlike core biopsies that sample only small regions and are likely less informative. However, multiple biopsies are impractical as they are very invasive and metastases can be difficult to access. Less invasive than tissue biopsies, liquid biopsies can be performed on blood samples. Blood-based liquid biopsies capture circulating tumor DNA (ctDNA) shed by tumor cells, which can reveal both spatial and temporal heterogeneity, and can capture examples of heterogeneity that single-tumor biopsies may miss. Includes histopathology, immunohistochemistry and fluorescence in situ hybridization (FISH) of tumor tissue. FISH detects the amplification or deletion of specific regions of chromosomes and can be used to focus on specific tumor cells. Such as whole-exome sequencing (all protein-coding regions) or whole-genome sequencing (coding and noncoding regions). These focus on large areas of the genome instead of particular loci and are more suitable for discovering new biomarkers. They can also detect differences missed by focused approaches but can suffer from low resolution. Single-cell analysis For example, single-cell RNA or DNA sequencing. These techniques are some of the most reliable and enable the study of cellular populations at a greater resolution. This explains why not all patients respond to treatment or why those that initially responded well eventually relapse, often with new tumors that no longer respond to that therapy. Issues surrounding heterogeneity in the clinic have emerged with the development of targeted therapies. Combining therapies that target the pre-dominant sensitive clones, as well as subsets of drug-resistant clones, are likely to have the most durable responses. Overall, heterogeneity fuels resistance and is linked to unfavorable outcomes. Cancers typically become more heterogeneous and complex with successive treatment exposures, which have worse responses than initial treatments. Intratumor These tumors feature distinct populations of tumor cells with varying genetic, epigenetic and phenotypic features. A type of “intrapatient” heterogeneity. This may explain, in part, why some successfully treated patients relapse, often with tumors that no longer respond to the original therapy. Intertumor Where individual tumors of the same type differ within the same patient – another type of “intrapatient” heterogeneity. This can arise from the original tumor spreading, with metastases stemming from the different “clones” featuring their respective characteristics. Established metastases can also evolve independently from one another. This can lead to different acquired resistance mechanisms existing in the same patient. Interpatient Where patients with the same cancer type have tumors that are not clinically similar. Patients with different tumor subtypes can have different biological behaviors and therefore very different outcomes. This can arise due to exposure to different microenvironments around the tumor, germline variants (that are passed from parent to child) or unique mutations within tumors (somatic variants). Heterogeneity is also linked to worse responses to treatments and unfavorable outcomes for patients. Let’s explore these concepts in more detail. Sponsored by Heterogeneous tumor Unsuccessful treatment Survival of resistant clone Repopulation of the tumor Homogeneous tumor Tumor cells are eliminated Successful treatment Response to therapy Tumor heterogeneity Diagnosis Relapse Treatment Time Clonal population Low heterogeneity High heterogeneity