Search

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 p

Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence beta III-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of beta III-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that beta III-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing beta III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of beta III-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that beta III-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients., National Health and Medical Research Council (NHMRC); Cancer Council New South Wales; Cure Cancer Australia Foundation Grant; Cancer Institute NSW Fellowship; NHMRC CDF Fellowship; NHMRC Senior Research Fellowship