Colorectal cancers (CRCs) rely heavily on host-derived structures to support tumour development and maintain growth. The tumour microenvironment (TME) includes contributions from underlying vascular endothelial cells to maintain nutrient and oxygen availability, as well as a delicate interplay with effector and suppressor immune cells to ensure effective immune evasion. Despite previous attempts to target these TME components through direct, individual therapeutic interventions targeting pro-angiogenic signaling and blocking immune suppression, in many cases the CRC TME remains supportive of tumour growth. Here, I have identified a loci-specific Autism Spectrum Disorder-linked 16p11.2 microdeletion, that demonstrates a negative impact on tumour growth. Initially, I show that a constitutive 16p11.2 deficiency (16p11.2df) alters tumour growth, although has no impact on tumourigenesis. Moreover, I demonstrate that a 16p11.2df in host- derived structures of the TME but not tumour cells is sufficient to slow tumour growth. Further, I demonstrate that vascular networks are altered in tumours derived from a 16p11.2df TME. While I present systemic alterations to the immunological landscape of 16p11.2df individuals at the transcriptional level, there is no detectable alteration in cytotoxic immune cell infiltration into 16p11.2df-derived tumours despite increased expression of T cell activating cytokines. In addition to altered growth characteristics, tumours derived from 16p11.2df mice show an enrichment in apoptosis of tumour cells, despite no change in proliferation. These findings suggest the potential for a 16p11.2df-mediated induction of tumour dormancy, through which volumetric tumour growth is slowed. Together, this study demonstrates the need for further investigation of the 16p11.2 microdeletion as a critical regulator of tumour growth.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/44061 |
| Date | 15 September 2022 |
| Creators | Haebe, Joshua |
| Contributors | Benoit, Yannick |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/ |
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