We study the functional links between two key intracellular processes: endocytosis and receptor signaling. We seek to understand how cells take up, transport, sort, and process different substances and signals, and how these rules of cellular logistics change under pathological conditions, such as cancer or selected rare diseases. We focus particularly on ESCRT complexes and AXL-dependent macropinocytosis, because disturbances in these processes may reveal vulnerabilities that can be exploited in targeted therapies. 

Research Summary

We are fascinated by how endocytosis and receptor signaling cooperate in healthy cells and in disease states. We investigate how endosomal compartments influence receptor trafficking and signaling, and how alterations in these processes support cancer progression or contribute to the pathogenesis of rare genetic diseases. 

One major research direction concerns the roles of endosomal sorting complexes required for transport, or ESCRT complexes, in cell physiology and oncogenesis. We have shown that endosomal dysfunction caused by loss of proper ESCRT function induces three types of cellular responses: sterile inflammatory signaling, lysosome biogenesis, and metabolic reprogramming towards enhanced use of extracellular nutrients. Together, these findings demonstrate a broad role of ESCRT complexes in coordinating membrane trafficking, signaling, and metabolism. 

The synthetic lethality we identified between two paralogous ATPases of the ESCRT machinery, VPS4A and VPS4B, has uncovered a new pair of potential therapeutic targets for personalized oncology. We also investigate how mutations in ESCRT components found in rare neurological disorders alter cellular functions and may underlie disease pathogenesis. 

In a separate line of research, we focus on macropinocytosis, one of the least characterized routes of endocytic cargo internalization. This pathway is nevertheless crucial for nutrient acquisition by cancer cells. We discovered that the AXL receptor tyrosine kinase, a receptor frequently overexpressed in late-stage and therapy-resistant cancers, is a potent inducer of macropinocytosis. 

Upon activation by its ligand GAS6, AXL drives extensive actin cytoskeleton remodeling, promoting the formation of dynamic membrane ruffles. These ruffles extend and close to generate macropinosomes - large, irregular vesicles containing extracellular fluid and associated cargo, such as nutrients, growth factors, and membrane receptors. Newly formed macropinosomes subsequently mature through sequential fusion and fission events with endosomal compartments, enabling the sorting, degradation, or recycling of internalized material. Building on our identification of AXL-interacting proteins, we are currently characterizing the effectors and regulators that mediate macropinocytosis.

Scientific Impact

Our studies provide proof of concept that intracellular trafficking and the molecules regulating it can represent viable therapeutic targets in personalized oncology. For example, the synthetic lethality between VPS4A and VPS4B ATPases provides a rationale for developing VPS4 inhibitors for the precision treatment of VPS4B-deficient cancers. 

At the same time, our ongoing studies of AXL-dependent macropinocytosis aim to uncover ways of blocking this process in metastatic and drug-resistant cancers with AXL overexpression. Work on mutations in ESCRT components found in rare neurological diseases also helps explain how disrupted cellular logistics can translate into pathology at the cellular and tissue levels. 

Future Goals

We wish to understand how altered expression or mutations of ESCRT components, observed in cancer and some rare diseases, modify cell physiology. In parallel, we aim to elucidate the mechanisms and effector proteins by which the activated AXL receptor drives macropinocytosis and fuels cancer-cell growth. 

Collaborations

We collaborate with partners from IIMCB and external institutions within the HERO consortium project, which aims to develop the next generation of mRNA-based cancer immunotherapies. Prof. Marta Miączyńska also coordinates the research area focused on advanced models of rare diseases in RACE-PRIME, a project aimed at developing innovative therapeutic strategies for diseases where current treatment options remain inadequate or unavailable. 

Comment

In 2024-2025, we continued to study the principles of cellular logistics: how cells take up and transport various substances within their interior, and which signals initiate these processes. Our aim was to understand how these trafficking rules are altered in disease, for example, in cancer cells with increased metabolic demands or in cells carrying mutations that cause rare genetic disorders. We believe that elucidating these underlying mechanisms can ultimately guide the development of new therapeutic strategies. - Prof. Marta Miączyńska 

Murine bone marrow-derived macrophages cultured in vitro. Nuclei are stained blue, endosomes green, nucleoli magenta, and actin gray. Image by Patrycja Daszczuk.

Transmission electron microscopy image of membrane organelles - a multivesicular endosome containing internal vesicles and mitochondria - in a HEK293 cell. Image by Ewelina Szymańska, Matylda Macias, Aleksandra Szybińska.