Periodic Reporting for period 3 - HoldCancerBack (What Holds Cancer Cells Back?)
Reporting period: 2020-08-01 to 2022-01-31
Current cancer research concentrates on the genetic and molecular level of individual cells. Molecular biology has revolutionized our understanding of cancer and provided overwhelming details. The reductionist approach of Physics of Cancer does not reach the depth of a molecular description, yet it leads to strong quantitative measures on an emergent level. To complement the molecular perspective, 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 pursues the next 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. I have been able to prove that cancer cell unjamming occurs in breast and cervix tumors. Cancer cell unjamming is new type of unjamming transition that differs from cell jamming in embryonic development. 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 phase that combines mechanical stability with a maximum of cancer cell motility. Cancer cell unjamming clearly fosters cancer cell escape from the primary tumor and is thus a very 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. The novel index complements the lymph node status, which is the current gold standard to evaluate metastatic risk and thus will avoid over and under treatment of patients. It is less expensive than novel gene signature based approaches. My prognostic index is “agnostic” to different tumor entities since it relies on general physical changes that trigger metastasis. Thus, we can address approx. 92% of all cancer incidents worldwide
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 the cancer cell clusters found in a solid tumor cancer cells collectively become motile through a novel unjamming transition and fluidize the tissue. My publication in Physical Review X on this topic has been chosen by Nature Review Physics as one of the ten most important physics publications in 2021 and by Physical Review X as one of the ten most important experimental publications of the last ten years. Unlike cell jamming in embryonic development, which is driven by an increase in cell density, cancer cell unjamming is based on elongated cell and nucleus shapes (CeNuS) as well as a decrease in nucleus density (Blauth et al, Frontiers in Physics (2021)). 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 1 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 (manuscript submitted to Nature Physics, https://doi.org/10.21203/rs.3.rs-1114106/v1). 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. A change from cortical contractility to stress fiber based contractility also plays a role in the unjamming process (Warmt et al, New Jour. of Phys. (2021)). Other key drivers of unjamming and cancer cell escape from the tumor mass are stroma density and cadherin expression (Ilina et al, Nature Cell Bio. (2020)). Since cancer cell unjamming is probably the earliest event of the metastatic cascade. I have investigated its prognostic value for distant metastasis. My clinical data obtained in a retrospective study of histological slides from 1,380 breast cancer patients demonstrate that cancer cell unjamming is of prognostic relevance concerning distant metastasis (manuscript submitted to Nature Materials, Fig 2. 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 marker for the prognosis of 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.
I will strive to ensure that my results 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 moderate concordance. Besides my specific clinical goals, I intend to demonstrate that a systemic disease, such as cancer, needs convergent science, including the Physics of Cancer, to be fully addressed. My project may thus exemplify a change to convergent science in oncology.