Teleological thinking (i.e. the existence of goals and purposes) and agential thinking (i.e. an entity making rational decisions) are still common in biology. In physics, for example, no one thinks of the Sun's purpose or gravity's goal. However, in biology, we use agential words like ‘manipulate,’ ‘function,’ ‘role,’ and so on as if a cell or organism has a goal or purpose. These views constrain our understanding of biology, including cancer.

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Tissues are fundamental compartments in our body. The initiation of a tissue developmental process in various organs has been studied well. On the other hand, our knowledge of how the process ends is limited. The fundamental question is whether any goal exists. The state that appears as a goal could be an equilibrated state. In development, epithelial-mesenchymal interaction drives tissue morphogenesis. Through this interaction, the formation of the basal membrane underneath the epithelium is initiated, which physically separates epithelial and mesenchymal cells, leading to a stable equilibrated state that appears to be a goal. However, if the physical barrier is compromised, the epithelial-mesenchymal interaction is revoked until it returns to the equilibrated state. For example, wound healing always has an end because it reaches back to this stable state. This is a very important perspective.

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Over a century ago, Virchow saw cancer as a non-healing wound. The question is why this wound does not heal. When a cell senses a danger, it alerts its neighbours. This alert is inflammation. The first cell type that responds to the alert is called tissue residential macrophages (TRMs). Depending on the amplitude of inflammation, TRMs recruit helpers from the circulation or deal with it by themselves to restore the original condition. The tasks of TRMs are clearing the inflammatory cell and remodelling the basal membrane to initiate epithelial-mesenchymal interaction that leads to the restoration of the stable equilibrated state. If the inflammation is not cleared, remodelling will continue. This would be the non-healing wound.

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What are the dangers that each cell can sense? One is leaked biological materials from dead cells. TRMs quickly clear them. The other is pathogens, like bacteria and viruses. They can be removed by TRMs before entering into a cell. Even after they enter a cell, our cells have mechanisms to sense them, called innate viral detection systems. In our cells, DNA is stored in the nucleus or mitochondria. RNA in the cytoplasm is the single-strand and uniquely decorated. In other words, DNA in the cytoplasm, double-stranded RNA or RNA without decoration is sensed as viral infections. The viral infected cells sense those viral properties and initiate inflammation. Simultaneously, the virus takes over the translational machinery to produce its unique viral peptides. Activating inflammation and presenting the unique viral peptides allow T-cells to recognize the infected cells to be killed.

 

My central hypothesis is that cancer is caused by chronic low-grade sterile inflammatory somatic cells created by false activations of the viral sensing innate immunity, forcing the engagement of TRMs that keep remodelling the basal membrane, leading to the constant activation of developmental programs. This view provides a new perspective into the current epidemiological concerns toward chronic low-grade sterile inflammatory conditions like obesity, shift work, alcohol, etc. The chronic low-grade sterile inflammatory condition forces TRM engagement for remodelling the basal membrane that facilitates epithelial cells entering the cell cycle. The accumulation of genetic/genomic changes is inevitable due to DNA replication and mitosis in inflammatory stressful conditions. Genetic/genomic changes are not the cause of malignancy but are the consequence of the cycle of DNA replication and division under stressful conditions.  

 

Aim1: Investigating the importance of the false activation of the innate viral sensing mechanism, the cGAS/STING pathway in malignancy

We hypothesize that the fundamental difference between malignant and benign tumours is whether the cell has the false activation of the innate viral sensing mechanism. To test this, we are generating the conditional constitutive activation allele of Sting that can falsely activate innate viral sensing. We will create benign tumours in this transgenic mouse line to determine if STING activation is sufficient to make them malignant without any new mutations. We speculate that the activation of STING in benign tumours is sufficient to make them malignant without new mutations.

 

Aim2: Investigating the development of tumour microenvironment from the normal microenvironment

We hypothesize that the engagement of tissue residential macrophages and the mutual interaction between the malignant cells and tissue residential macrophages are essential for developing the tumour microenvironment. This interaction itself is malignancy. We have a tool to label tissue residential macrophages for isolation and specific manipulations. We will investigate how they react with malignant cells. We speculate one of the key molecules derived from tissue residential macrophages is interleukin-6 (IL-6). We will eliminate IL-6 from tissue residential macrophages to investigate their contribution to establishing the tumour microenvironment.

 

Somatic mutations are not directly involved in malignancy but in proliferation and stress compensations during the disease progression. Understanding mutations will never reach the understanding of malignancy because malignancy is a different dimension from mutations and proliferation. Mutations and proliferation are a part of malignancy but not the malignancy itself. Malignancy is a chronic low-grade sterile inflammation of somatic cells. This is why it progresses silently without being noticed until reaching our homeostatic system's tipping point.