Biology subjects

Bacchetti, R.

Publications and source records attributed to Bacchetti, R..

4 recordsLinked to original sources

bioRxiv2026

Oncogenic RAS-driven α2 integrin induction under nutrient stress promotes cancer cell motility

Cancer metabolism rewiring is one of the hallmarks of cancer, enabling cancer cell survival in a nutrient deprived microenvironment. Key to this is nutrient scavenging where cancer cells rely on extracellular proteins, including extracellular matrix (ECM) components, to sustain their proliferation. ECM uptake is mediated by 2{beta}1 integrin, however it is not clear how this process is controlled by nutrient availability. Here we demonstrated that amino acid starvation promoted ECM internalisation, by inducing the expression of 2 integrin. Mechanistically, starvation-driven RAS/MAPK pathway activation in cells harbouring oncogenic RAS mutations and mTOR inhibition increased 2 integrin, while the GCN2-depedent integrated stress response was not required. Functionally, elevated 2 integrin levels promoted cell adhesion and migration in nutrient starved cells. Finally, 2 integrin was found upregulated in pancreatic tumours and correlated with poor prognosis in pancreatic adenocarcinoma patients. Together, these data indicate that the nutrient- starved pancreatic cancer microenvironment synergises with KRAS mutation to drive pancreatic cancer aggressiveness.

cancer biology↗

bioRxiv2024

Cryptosporidium Oocyst Wall Proteins are true oocyst wall proteins, with COWP8 functioning to hold the inner and outer layers of the oocyst wall together

Cryptosporidiosis is a significant cause of diarrhoeal disease contributing to substantial morbidity and mortality for the immunocompromised and for young children, especially those who are malnourished. There are no vaccines available and no effective treatments for these patients. Another challenge is that Cryptosporidia are waterborne and resistant to common water treatments including chlorination. Cryptosporidia are transmitted as an oocyst that is made up of a hardy oocyst wall that protects four parasites. Little is understood about how the oocyst is constructed, its composition, and the how it resists chlorination. A family of predicted Cryptosporidium Oocyst Wall Proteins (COWPs) was identified from the genome. Using a genetic approach, we confirm that all members of the COWP family localise to the oocyst wall. Our studies indicate that COWP2, 3 and 4 localise specifically to the oocyst "suture", a zipper-like structure on the oocyst wall from which parasites emerge during infection. In parasites lacking COWP8, we observe that the inner and outer layers of the oocyst wall are no longer associated suggesting a role for COWP8 in oocyst wall morphology. Despite loss of COWP8, these transgenic parasites are viable, unchanged in mechanical strength, and retain resistance to chlorination. This work sets the foundation for future exploration of Cryptosporidium transmission.

microbiology↗

bioRxiv2024

The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25.

Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5-year survival rate of less than 30% in the presence of metastasis. Metastatic progression is characterised by extensive remodelling of the extracellular matrix, primarily mediated by secreted matrix metalloproteinases, including members of the a disintegrin and metalloprotease with thrombospondin motif (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated in ovarian malignant tumours compared to borderline and benign lesions, suggesting it might play a role in metastatic progression. Furthermore, it has been suggested that Rab25, a small GTPase of the Ras family, might upregulate ADAMTS5 expression in ovarian cancer cells. Here we demonstrated that Rab25 promotes ADAMTS5 expression, through the activation of the NF-{kappa}B signalling pathway. Furthermore, ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through complex fibroblast-secreted matrices, while ADAMTS5 inhibition prevented ovarian cancer spheroid invasion in 3D systems. Finally, in ovarian cancer patients high ADAMTS5 expression correlated with poor prognosis. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a novel therapeutic target to prevent ovarian metastasis.

cancer biology↗

bioRxiv2024

Internalisation of integrin-bound extracellular matrix modulates invasive carcinoma cell migration

The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While the extracellular degradation of ECM proteins has been well characterised, ECM endocytosis and its impact on cancer cell progression, migration and metastasis is poorly understood. ECM internalisation is increased in invasive breast cancer cells, suggesting it may support invasiveness. Here we developed a high-content screening assay to study ECM uptake. We identified that mitogen-activated protein kinase (MAPK) family members, MAP3K1 and MAPK11 (p38{beta}), and the protein phosphatase 2 (PP2) subunit PPP2R1A were required for the internalisation of ECM-bound 2{beta}1 integrin. Furthermore, 2{beta}1 integrin was necessary for macropinocytosis of soluble dextran, identifying it as a novel and targetable regulator of macropinocytosis in cancer. Moreover, disruption of 2 integrin, MAP3K1, MAPK11 and PP2R1A-mediated ECM internalisation significantly impaired cancer cell migration and invasion in 2D and 3D culture systems. Finally, 2{beta}1 integrin and MAP3K1 expression were significantly upregulated in pancreatic tumours and correlated with poor prognosis in pancreatic cancer patients. Strikingly, MAP3K1, MAPK11, PPP2R1A and 2 integrin expression were higher in chemotherapy-resistant tumours in breast cancer patients. Our results identified the 2{beta}1 integrin/p38 signalling axis as a novel regulator of ECM endocytosis, which drives invasive migration and tumour progression.

cancer biology↗