The fundamental goal of my laboratory is to answer this question. Currently, two major theories dominate the theoretical framework for understanding cancer: 1) The Stem cell theory of cancer and 2) the Genetic/Clonal evolution theory. The clonal evolution model of tumor formation suggests that tumors arise from the accumulation of mutations in a single cell, which undergoes clonal expansion, leading to tumor heterogeneity and competition between clones over time. In contrast, the cancer stem cell model posits that tumors are driven by a small population of self-renewing, stem-like cancer cells that maintain and propagate the tumor, with a focus on the hierarchical nature of tumor cells. These CSCs do not necessarily have a different genotype to the rest of the tumour mass. Much recent work has been to reconcile these two theories - for example a tumour could have both a clonal structure and a stem cell niche simultaneously. However, it is my belief that even a combined model of both is incomplete. These theories fall short because neither theory effectively take account of the historical contingencies of the tissue (i.e. the development those tissues went through to become what they are). I believe this feature is crucial to include in any theory of cancer to fully understand what is happening and to develop appropriate treatments.

Instead, i am developing the 'Emergent theory of cancer'. This theory heavily involves the idea that the mechanisms (such as morphodynamic pattern forming mechanisms) used during development switch back on abnormally due to the distributed tissue insult that accumulates with aging. The fundamental cause is identical to the other mechanisms (genomic mutation, tissue insult etc) but the effect on the organ as a whole or large proportion of the organ is totally different. In the ETC most of an organ can in theory be healthy as defined by the other theories in that they have no mutations, however due to signalling and the switching back on of developmental mechanisms they may well be contributing to a carcinogenic signalling environment. As such a large swathe of the tissue is 'primed' for tumorogenesis such that killing and/or removing the part of the organ that is considered cancerous does not solve the problem since it will highly likely recur. I believe this is the reason for such high recurrence rates in cancer and the principal reason why we still have such poor prognosis for many solid cancers.

This theoretical framework involves a paradigm shift in mindset from viewing a cancer as involving a small proportion of the tissue to instead involving much larger swatches of the organ that appear normal both visually and by classic cancer defining criteria. Indeed, in order to cure cancer i believe that the 'sick' but normal looking organ tissue needs our attention as much as the cancer part that we have killed or cut out. This paradigm shift also involves a shift from focusing solely on key mutations at specific locations in genes (think Kras G12D) to mutations with minor effects distributed over a tissue that have accumulated with age and that in culmination result in the switch in the tissue behaviour so that abnormal signalling occurs with its roots in developmental mechanisms. Overall, approaching cancer in this way suggests a revolutionary strategy for combating cancer, by not only eliminating the primary tumour but also restoring tissue health through orthotopic implantation of personalized engineered differentiated tissue derived from autologous iPS cells to prevent tumour recurrence.

There is already some evidence for the ETC in the existance of neoplasms. A good example are PanINs that form the prerequisits for pancreatic ductal adenocarcinoma. Under the ETC a pancreas showing extensive and advanced panINs would already be considered cancerous and any effective anticancer treatment requires this tissue to be treated to reduce the frequency of the panINs. This project will involve further exploring more subtle features of tissue not considered cancerous but which primes the tissue for the development of what is considered classically a tumour.

This project will involve performing single cell spatial genomic and transcriptome sequencing of Mouse and Human Tumour and normal tissue. I am expecting to observe particular phenomena if my thesis is correct. Further, development of technique for performing spatial genomics and transcriptomics (see project 2) will aid in furthering this project. In the mouse setting the aim is to obtain a cohort of ageing wildtype mice that were due to be sacrified from the projects of other laboratories (Therefore applying the reduction of the 3Rs). These mice will be monitored for the accumulation of particular mutations and insults to various tissues of interest. Furthermore, they will serve as cohorots for preclinical trials for the therapies i aim to develop (see below). In the human setting i will apply to biobanks for tissue from both cancer and normal tissue from ageing individuals to see if the particualr genetic and distributed tissue insults i expect from the ETC are evident.

Finally, I aim to flesh out this theory by developing an explicit computational model. This model should also clarify the distinction between the ETC and the Clonal and CSC models of tumourogenesis and may even allow us to map out the space of primary tumorigenesis mechanisms. I will utilize agent based computational models of differing levels of abstraction for this project.

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