Understanding the role of the cytoskeleton in tumor progression

Benign Prostate and Prostate Cancer
AIM1 (red) and actin (green) show dramatic changes in abundance and subcellular localization in benign tissues and prostate cancers.

Cancer’s most feared feature is its ability to invade into benign tissues and spread to distant sites. Prostate cancer, for instance, can travel to any part of the body; most commonly to lymph nodes and bones where it is very challenging to treat. To intercept the process of cell invasion and metastasis formation with new therapies, we need to understand how tumor cells migrate and spread through the body.

Every cell has a structural scaffold, a skeleton termed the cytoskeleton. It consists of a complex interlinked network of proteins that supports the cell and helps to maintain its shape. To invade other tissues, cancer cells need to alter their cytoskeletal properties to become malleable enough to change their shape and to move through tissues. However, the process by which cancer cells become such “shape shifters” is not well understood.

We have recently unmasked an important protein, named AIM1 that regulates the cytoskeleton in benign cells and is dysfunctional in cancer (see Haffner et al., Nature Communications, 2017). When AIM1 is present, the cells' scaffolding keeps it rigid and correct shape. When AIM1 is lost, cells can remodel their cytoskeleton more frequently change their shape and become capable of invading and migrating to distant locations. Notably, in preliminary studies we find that the AIM1 gene is frequently lost or mutated in aggressive forms of prostate cancer. We therefore hypothesize that by losing AIM1 prostate cancer cells gain the ability to change shape, migrate, invade and to spread to different tissues.

More broadly, we are interested in examining the relationship between the cytoskeleton and cancer cell invasion and metastasis formation. The ultimate goal of this research is to develop new and innovative therapies that allow us to specifically target cancers with cytoskeletal alterations. To this end we will perform a cutting-edge genetic screen that unmasks vulnerabilities in cancer cells that can be used as novel drug targets.

Investigating DNA methylation alterations in advanced prostate cancer

All cells in the human body have the same DNA sequence; but a cell in the heart looks and functions very differently than a cell in the prostate. These differences are dictated by an additional layer of information that is encoded by modifications of the DNA molecule that do not change the DNA sequence. Such epi-genetic marks (literally meaning on top of the genome) define the function and behavior of all cells. Of the many epigenetics marks that are currently known, DNA methylation, which involves the addition of a chemical group directly on the DNA molecule, is the best studied. DNA methylation is essential for cellular differentiation and determines the fate of a cell. Although essential for every cell in the human body, cancers find unique ways to highjack and change these epigenetics marks. Prostate cancers in particular show major DNA methylation changes. We therefore reason that by understanding the pattern of DNA methylation changes in prostate cancer, we can identify unique vulnerabilities that would allow us to treat prostate cancers more effectively. To this end we use an integrated approach, combining both in situ and next generation sequencing based methods to comprehensively analyze DNA methylation alterations in advanced metastatic prostate cancer.


Metastatic prostate cancers can exhibit a broad spectrum of DNA methylation alterations. Profound global loss of DNA methylation can be detected in tissue sections.

LuCaP graph

Cutting-edge next generation sequencing methods allow the detailed mapping of DNA methylation changes.

Distant Metastasis
Primary prostate cancers are known to be multiclonal. Individual tumor clones can show dramatically different biological and clinical behaviors.

Deciphering intra-tumoral heterogeneity and its impact on diagnosis and therapy

It is well accepted that every patient’s cancer shows unique genomic and phenotypic changes. However, over the past years several studies have highlighted the high level of genetic and phenotypic heterogeneity within a given tumor (see Haffner et al., Nature Reviews Urology, 2020). It is increasingly recognized that prostate cancers that develop resistance to contemporary therapies exhibit a diverse spectrum of disease phenotypes. In particular, the used of highly potent second-generation hormonal therapies such as abiraterone and enzalutamide has led to the emergence of cancer phenotypes that are divergent from conventional prostate cancers. Such divergent molecular evolution in response to therapy results in a high level of diverse cell populations with differences in many measurable traits including proliferation, metastatic potential and therapeutic resistance. This heterogeneity poses important challenges for the diagnosis and treatment of advances prostate cancer, but the extent, biological context and clinical relevance of inter-individual heterogeneity is unknown. To formally define the extent and clinical relevance of tumoral heterogeneity, we aim to carefully assess the pattern of molecular features within and between different metastatic sites in patients with metastatic prostate cancer.