Periodic Reporting for period 4 - HoldCancerBack (What Holds Cancer Cells Back?)
Période du rapport: 2022-02-01 au 2023-04-30
Cancer research concentrates on the molecular properties of individual cells, which has revolutionized our understanding of cancer and provided overwhelming details. The reductionist approach of Physics of Cancer does not reach the same depth in detail, yet it leads to quantitative measures and provides understanding on an emergent level, which cannot be described by bottom up approaches such a molecular description. To complement the available molecular information, the project focuses on the collective behavior of cancer cells and answers the question: When is a cancer cell jammed or when can it overcome the yield stress to actively “flow” in a dense microenvironment? The PI has brought forward the basic idea within the concept of Physics of Cancer that changes in a cancer cell’s and/or a tumor tissue’s mechanical properties determine its metastatic potential. The project has achieved a breakthrough in the Physics of Cancer by determining the role of cancer cell unjamming in the metastatic cascade and by deriving a predictive diagram to mark the conditions for unjamming transitions of cancer cells (see Fig 1). I have been able to prove that cell unjamming occurs in breast and cervix tumors. It is new type of unjamming transition that differs from jamming in inanimate soft matter. I have generated a state diagram that determines as a function of shape (cell and nucleus shape (CeNuS)) and nucleus spacing whether a cellular tissue is collectively jammed or motile. This is the basis of my new prognostic criteria for distant metastatic risk. The diagram solves open questions concerning the cell unjamming process. The contribution of the cell nucleus has been previously unknown. The diagram reconciles the controversial roles of shape and packing by combining them in the state diagram. Within a solid tumor the cancer cell clusters embedded in stroma show solid, areas of jammed cells surrounded by fluid regions of motile cancer cells forming a heterogeneous solid that combines mechanical stability with a maximum of cancer cell motility. Cancer cell unjamming fosters cell escape from the primary tumor and is thus an early event of the metastatic cascade. In a retrospective clinical trial with 1380 breast cancer patients I have shown that cancer cell unjamming is the basis of a new prognostic index for distant metastatic risk, which complements the lymph node status, the current gold standard for metastatic risk, and thus will avoid over and under treatment of patients. My prognostic index is “agnostic” to molecular details of different tumor entities. Thus, we can address approx. 92% of all cancer types.
In Grosser et al, Physical Review X (2021), my lab has shown in patient derived tumor explants of cervix and breast carcinoma by vital cell tracking that in cancer cell clusters cells collectively become motile through a novel unjamming transition and fluidize the tissue. Our publication has been chosen by Nature Review Physics as one of the ten most important publications in 2021 and by Physical Review X as one of the ten most important publications of the last ten years. Based on previous findings cell unjamming was either interpreted shape or density induced (Blauth et al, Frontiers in Physics (2021)) my state diagram resolves this conflict (Fig 2). Cancer cell unjamming is based on elongated cell and nucleus shapes (CeNuS) as well as a decrease in nucleus number density. The phenomenon of cancer cell unjamming allows me to develop the first clinical cell motility marker that can be used in static images such as histological slides as illustrated in Fig 3. I have shown that the cancer cell clusters embedded in stroma within solid tumors need jammed regions of stiff cancer cells to behave like a mechanically stable solid and unjammed regions of soft, motile cells to foster motility and proliferation (Fuhs et al, Nature Physics (2022)). The cancer cell clusters assume a unique heterogeneous solid state, where the soft unjammed cells are the majority and tension percolation generates a solid behavior. Jammed and unjammed cells differ by a decrease in cell stiffness (see Fig 4). A change from cortical contractility to stress fiber based contractility plays a role in the unjamming process (Warmt et al, New J. Phys. (2021)). Other drivers of unjamming and cancer cell escape from the tumor mass are stroma density and cadherin expression (Ilina et al, Nature Cell Biol. (2020)). Cancer cell unjamming is one of the earliest events in the metastatic cascade. I have investigated the prognostic value of cancer cell unjamming for distant metastasis. Our retrospective study of histological slides from 1,380 breast cancer patients demonstrates that cancer cell unjamming is of prognostic relevance concerning distant metastasis (Gottheil et al, Physical Review X (2023)) (Fig 5). The Nottingham index is currently the gold standard in prognostic indices, relying on histopathology. It uses the invasion of nearby lymph nodes as the sole indicator of cancer cell motility. Thus, lymph node status constitutes the most important prognostic marker for distant metastases. Cancer cell unjamming distinctively complements the lymph node status. Unjamming seems to support pathways for distant metastasis that bypass the lymph nodes. Thus, jamming may help to avoid overtreatment of patients with false-positive lymph nodes and under treatment of patients with false-negative lymph nodes with regard to metastatic risk. Moreover, on a bulk level cancer cell unjamming causes an increase in tissue fluidity. In collaboration with Prof Sack’s lab at the Charité I have shown for a broad range of tumor entities that tumor progression leads to tissue fluidization, which can be used a prognostic criterion in magnetic resonance elastography (MRE) (Sauer et al, Adv. Science, in press).
I have fully achieved the goals of the project. In terms of tumor biology, cell unjamming is a quintessential part of the metastatic cascade. While recent publications about the epithelial mesenchymal transition as onset of cell motility present an ambivalent picture, unjamming plays a clear role in cancer cell motility. The cell unjamming is a fundamentally new process in soft matter physics and creates in tumors a new state of matter that combines a solid bulk behavior with a dominant fraction of motile cells. Our clinical breast cancer trial proves that cancer cell unjamming can serve as a prognostic for distant metastatic risk in the clinic. Cell unjamming as prognostic marker provides complementary information to existing diagnostic approaches and will thus reduce over and under treatment of cancer patients. I am currently planning a large clinical study with 25,000 breast cancer patients and a clinical trial for colorectal cancer to further validate my prognostic approach. I will strive that my results on cancer cell unjamming will gain broad clinical attention so that further clinical studies will quickly establish cancer cell unjamming as a standard prognostic tool. Despite the merits of molecular biology, therapy decisions that consult gene expression tests do not necessarily result in a change in the survival rate. Up to now, these signatures show a moderate concordance index for their prognostic power. Besides my specific clinical goals, the project exemplifies that a systemic disease, such as cancer, needs convergent science, including the Physics of Cancer, to be fully addressed.