The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.

The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells use various adaptive mechanisms that may represent therapeutic targets. In this study, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPARδ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPARδ. Specifically, PPARδ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacologic inhibition of PPARδ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPARδ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a prometastatic phenotype in PDAC, suggesting that PPARδ inhibition could serve as a therapeutic strategy to combat PDAC progression. Significance: Nutrient starvation and microenvironmental signals activate PPARδ in pancreatic cancer to support survival and metastasis by promoting metabolic plasticity and invasiveness, providing a strong rationale for developing PPARδ-targeted therapies for pancreatic cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment.

The authors recently reported on the potential of targeting SRC kinase signaling in pancreatic cancer stem cells

Induction of EMT-like phenotype and metabolic switch in PDAC cells upon starvation. A, Representative images illustrating morphologic changes for PDAC-354 cells in response to treatment for 72 hours with the complex I inhibitor metformin (3 mmol/L), the β-oxidation inhibitor etomoxir (20 μmol/L), the complex II inhibitor malonate (5 mmol/L), the pyruvate carrier inhibitor UK5099 (100 μmol/L), or tumor-like conditions [low pH (HCl 50 μmol/L) + low glucose (1 mmol/L) + 3%O2]. Scale bar, 50 μm. B, Expression of EMT-associated genes (ZEB1, SNAI1, SNAI2, LOXL2, and VIM) was determined by RT-qPCR after cells were treated for 48 hours as indicated in A or with MCM. Pooled data for PDAC-185, A6L, 215, 253, and 354 (n ≥ 4 for each cell type). Data are normalized to HPRT1. Eto, etomoxier; Mal, malonate; Met, metformin. C, PDAC-215, 253, and 354 cells were treated with MCM or 20 μmol/L etomoxir for 48 hours and seeded in modified Boyden invasion chambers containing 20% FBS in the lower compartment. The number of invasive cells was analyzed after 16 hours (n = 7–11). D, GFP+-Luciferase+-PDAC-354 cells were treated with control, MCM, or 20 μmol/L etomoxir for 48 hours and then injected intrasplenically to assess their metastatic capacity (n = 9 mice/group). Representative photographs of liver metastasis (top) and subsequent hematoxylin and eosin staining (bottom). Scale bar, 200 μm. E, Representative OCR profile for PDAC-253 cells treated for 48 hours as indicated (mitochondrial stress test). O, ATP synthase inhibitor oligomycin; F, mitochondrial OXPHOS uncoupler FCCP [carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone]; A+R, complex III inhibitor antimycin A + electron transport change inhibitor rotenone. F, Maximal and ATP-linked respiration (resp) in non-CSC vs. CSC cells. Bars represent pooled data from PDAC-215, 253, and 354, showing individual data points corresponding to each PDX (n = 5–7). G, Representative extracellular acidification rate (ECAR) profile for PDAC-253 cells treated for 48 hours as indicated (glycolysis test). G, glucose; O, ATP synthase inhibitor oligomycin; 2DG, glycolysis inhibitor 2-deoxy-glucose. H, Glycolysis, glycolytic capacity, and glycolytic reserve in adherent (non-CSC) vs. sphere-derived cells (CSC). Bars represent pooled data from PDAC-215, 253, and 354, showing individual data points corresponding to each PDX (n = 4–5). All data are represented as the mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001. See also Supplementary Figs. S1–S3.

Expression of the PPAR family members and downstream targets after incubation with etomoxir and MCM