AMICO, REBECCA (2026) ADVANCED THERAPEUTIC STRATEGIES FOR COLORECTAL CANCER: FROM TARGET DISCOVERY TO PRECISION NANOMEDICINE. [Tesi di dottorato]

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Abstract

Colorectal cancer (CRC) and its peritoneal metastases (PM-CRC) remain associated with poor prognosis, largely due to metabolic plasticity, therapeutic resistance, and tumour heterogeneity. In this thesis, we investigated novel metabolic targets and explored strategies for selective therapeutic delivery using nanoparticles. Specifically, we identified the enzyme BAAT and its product, N-acyl taurines (NATs), as previously underappreciated regulators of CRC biology. BAAT is overexpressed in tumour tissues, and NAT accumulation modulates proliferation, migration, and clonogenic potential, indicating that the BAAT-NAT axis represents a biologically relevant and potentially targetable metabolic pathway. Moreover, we focused on FASN-dependent de novo lipogenesis in peritoneal metastasis-derived organoids (PMDOs). Inhibition of FASN disrupts mitochondrial cardiolipin composition, increases mitochondrial reactive oxygen species (mROS), and sensitizes tumour cells to apoptosis, thereby overcoming intrinsic resistance to oxaliplatin. These results highlight a metabolic vulnerability that can be therapeutically exploited and position FASN as a complementary target to BAAT in constraining CRC progression and metastasis. Finally, we explored strategies for tumour-selective nanoparticle delivery. Uptake of hyaluronan-functionalized nanoparticles (HA-NPs) by PBMCs from CRC patients is dictated by CD44 functional activation rather than total receptor levels. Constitutively active CD44 and tumour-associated variants drive selective nanoparticle internalization, providing a mechanistic basis for delivering therapeutic payloads, including small molecules, RNA-based drugs, or metabolic modulators, directly to tumour cells while sparing healthy tissues. Collectively, this thesis demonstrates that integrating metabolic targeting (BAAT and FASN) with receptor-mediated nanoparticle selectivity provides a rational, multi-layered strategy for precision therapy in CRC and PM-CRC. These findings lay the groundwork for combinatorial approaches that exploit tumour-specific vulnerabilities, enhance therapeutic efficacy, and minimize off-target effects.

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