Castanho Martins, Maria Inês; (2025) Small intestine neuroendocrine tumours: pathogenesis and potential targets in mesenteric fibrosis and liver metastasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Small intestine neuroendocrine tumours (SI-NETs) are rare cancers with rising incidence. Patients have a significantly higher incidence of liver metastasis (LM) development compared to other NETs, impacting survival. Mesenteric fibrosis (MF) causes severe desmoplastic reaction in the mesentery with great burden to quality of life and survival. SI-NET specific pathophysiology for LM and MF are not well described and pharmacological therapies are lacking, which is aggravated by lack of appropriate disease models. To address this, a model of SI-NET MF was developed using primary fibroblasts and GOT1 (cancer cell line) spheroids embedded in a hydrogel made from decellularized SI-NET patient tissue (non-fibrotic or fibrotic). Potential genes involved in MF were selected from RNA sequencing and DNA methylation data from an MF cohort and genes were tested on the MF hydrogel model and through functional tests using siRNA knockdown. The role of the PNPLA3 rs738409 mutation was investigated in the formation of the liver pre- metastatic niche by using a conditioned media co-culture model with GOT1 and PNPLA3-genotyped primary hepatic stellate cells (HSCs). Results showed the SI-NET MF hydrogel model was able to modulate expression of fibrosis- and cancer-associated genes in fibroblasts and GOT1, when compared to 2D cultures. RNA sequencing revealed enrichment of fibrosis, fibroblast and inflammation reactomes in samples of mesenteric metastasis and more severe fibrosis. MF candidate genes CTHRC1, THBS1 and CTSK were expressed by primary SI-NET fibroblasts and significantly increased expression when grown in fibrotic matrix hydrogels. Functional studies further confirmed their modulation of fibrosis-associated genes. The SI-NET LM model revealed mutant HSCs induced the expression of pro-tumourigenic and pro- metastatic genes in SI-NET cancer cells, while GOT1 induced a pro-inflammatory profile in HSCs. Overall, this work established a well-needed human SI-NET model, identified novel genes involved in MF pathophysiology and established potential targetable pathways in SI-NET LM.

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