Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming

Abstract

Omental metastasis occurs frequently in gastric cancer (GC) and is considered one of the major causes of gastric cancer-related mortality. Recent research indicated that omental adipocytes might mediate this metastatic predilection. Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) was identified to have a crucial role in metastasis. However, whether PITPNC1 participates in the interaction between adipocytes and GC omental metastasis is unclear.Methods: We profiled and analyzed the expression of PITPNC1 through analysis of the TCGA database as well as immunohistochemistry staining using matched GC tissues, adjacent normal gastric mucosa tissues (ANTs), and omental metastatic tissues. The regulation of PITPNC1 by adipocytes was explored by co-culture systems. By using both PITPNC1 overexpression and silencing methods, the role of PITPNC1 in anoikis resistance and metastasis was determined through in vitro and in vivo experiments.Results: PITPNC1 was expressed at higher rates in GC tissues than in ANTs; notably, it was higher in omental metastatic lesions. Elevated expression of PITPNC1 predicted higher rates of omental metastasis and a poor prognosis. PITPNC1 promoted anoikis resistance through fatty acid metabolism by upregulating CD36 and CPT1B expression. Further, PITPNC1 was elevated by adipocytes and facilitated GC omental metastasis. Lastly, in vivo studies showed that PITPNC1 was a therapeutic indicator of fatty acid oxidation (FAO) inhibition.Conclusion: Elevated expression of PITPNC1 in GC is correlated with an advanced clinical stage and a poor prognosis. PITPNC1 promotes anoikis resistance through enhanced FAO, which is regulated by omental adipocytes and consequently facilitates GC omental metastasis. Targeting PITPNC1 might present a promising strategy to treat omental metastasis.

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

“…3a), supporting our hypothesis that ATOH8 high CTCs is prone to survival in the circulation. On the other hand, our previous studies have found that metabolic reprogramming is a key factor mediating the anoikis resistance of tumour cells [24]. Further, to explore the association between metabolism and the ATOH8 mediated CTC survival, ssGSEA analyses were performed, and the data revealed that only glycolysis, a vital metabolic pathway in tumour cells, was significantly different between ATOH8 high and ATOH8 low , rather than fatty acid metabolism, oxidative phosphorylation and amino acid metabolism ( Fig.…”

“…BALB/c female nude mice 4-5 weeks of age were purchased from the Experimental Animal Centre, Southern Medical University (Guangzhou, China) and maintained in specific pathogen-free conditions. Subcutaneous tumour and metastatic tumour mouse models were generated as described previously [24]. Details are available in the supplementary materials (Additional file 1: Supplementary methods and materials).…”

MSC-induced lncRNA HCP5 drove fatty acid oxidation through miR-3619-5p/AMPK/PGC1α/CEBPB axis to promote stemness and chemo-resistance of gastric cancer

“…It has been reported that facilitation of FAO contributed to the resistance of cancer cells to drugs and aggravated tumorigenesis [25][26][27][28][29][30] . Previous works have associated FAO to GC by demonstrating that FAO induced the metastasis and that MSC co-culture aggravated FAO and improved stemness and chemoresistance in GC 31,32 . Therefore, it was reasonable to deduce that HCP5/miR-3619-5p could regulate FAO in GC.…”

“…uncovered to play a role in chemo-resistance, stemness, and tumorigenesis in cancer cells [27][28][29][30] . Also, it has been proved that the facilitated FAO can induce metastasis, confer chemo-resistance and improve stemness of GC cells 31,32 . Thus, we hypothesized that MSC-activated HCP5/miR-3619-5p regulated FAO in GC cells.…”

“…Furthermore, FAO is delineated to support stem cell property and chemo-resistance of cancer cells 27 , and repression of FAO impairs stemness and tumorigenesis [28][29][30] . In GC, the facilitated FAO is supported to aggravate the omental metastasis 31 . Interestingly, a recent study points out that MSC co-culture activates FAO in GC cells, leading to enhanced chemo-resistance 32 .…”