Metabolically rewiring pancreatic stromal cells in pancreatic cancer

Pancreatic cancer (PC) is a lethal malignancy characterised by chemoresistance and metastatic spread. This is largely due to the presence of dense stromal fibrosis which distorts tumour vasculature. This limits nutrient, oxygen and chemotherapy perfusion into pancreatic tumours and promotes oxidative stress. The craftsmen of fibrosis are cancer-associated pancreatic stellate cells (CA-PSCs) who drive disease progression, chemoresistance and metastasis. To survive in the tumour microenvironment, CA-PSCs and PC cells undergo significant metabolic changes. A key alteration is increased expression of nutrient transporters to promote nutrient uptake. Solute carrier transporters have gained significant attention as a novel class of therapeutic targets, particularly solute carrier transporter 7A11 (SLC7A11) and solute carrier transporter 7A5 (SLC7A5), which are upregulated in PC cells and CA-PSCs. This study aimed: (1) to assess SLC7A11 inhibition in cancer-associated pancreatic stellate cells in vitro and in a clinically relevant orthotopic mouse model of PC; and (2) to investigate the function of SLC7A5 and SLC3A2 in cancer-associated pancreatic stellate cells in vitro. This study demonstrated that inhibiting SLC7A11 in CA-PSCs reduced proliferation. This limited cystine uptake, glutathione synthesis and anti-oxidant capacity of CA-PSCs and sensitised to oxidative stress. In a co-culture setting, inhibiting SLC7A11 in both PC cells and CA-PSCs significantly reduced colony number. We evaluated the therapeutic efficacy of two different SLC7A11 inhibitors, sulfasalazine and erastin. Sulfasalazine proved ineffective at reducing orthotopic pancreatic tumour growth, indicating it cannot be repurposed as PC therapy. Excitingly, erastin showed significant anti-proliferative effects in both PC cells and CA-PSCs. In CA-PSCs, the anti-proliferative effects were mediated by the induction of both ferroptosis and apoptosis. Lastly, we observed inhibition of SLC7A5 in CA-PSCs reduced proliferation by inducing senescence and limiting leucine uptake. In summary, this thesis demonstrated inhibition of SLC7A11/SLC7A5 has the potential to target PC cells and CA-PSCs, representing a dual targeting approach. Our data supports the concept of personalised medicine in which a patient will be treated based on their tumour’s genetic/metabolic profile, overcoming the current ‘one-drug-fits-all’ approach. Importantly, our findings could be translated to other hard to treat solid tumours.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2019

Author dc:creator

• Akerman, Anouschka

• Pancreatic cancer
• Metabolic rewiring
• Pancreatic stromal cells

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/3890

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/64923