Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis.

Tumor-microenvironment factors and cancer stem cells (CSCs) play a critical role in the aggressiveness of pancreatic cancer (PC). However, the degree to which tumor-microenvironment factors promote stemness remains unexplored. Here, we examined whether cancer-associated fibroblasts (CAFs) promote CSC features in PC. PC cells were treated long-term (30, 60, and 90 days) with conditioned media (CM)-derived from normal human fibroblasts (NFs) and CAFs. The stemness features of tumorsphere formation and stemness populations, along with CSCs markers, were analyzed using 2-dimensional and 3-dimensional sodium alginate bead-based co-culture models. Immunohistochemistry and immunofluorescence staining were performed for CSCs and fibroblast markers in autochthonous KrasG12D/+; Trp53R172H/+; Pdx1-Cre mice and human pancreatic tumors. Polymerase chain reaction array and gene knockdown were performed to identify the mechanism of stemness enrichment. Long-term treatment of PC cells with CAF-CM enriched stemness, as indicated by significantly higher CD44+, ALDH+, and AF+ populations in PC cells. Increased tumorsphere formation and elevated CSC, self-renewal, and drug-resistance markers in CAF-CM-treated PC cells were observed. In addition, CAFs co-cultured with PC cells in the 3-dimensional model showed a substantial increase in stemness features. CD44 and α-smooth muscle actin were positively correlated and their expressions progressively increased from the early to late stages of KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse and human pancreatic tumors. Osteopontin/secreted phosphoprotein 1 was identified as the top differentially overexpressed gene in CAF-CM-treated PC cells and knockdown of osteopontin/secreted phosphoprotein 1 significantly reduced stemness characteristics in CAF-CM-treated PC cells. Our data uncovered novel insight into the interplay between CAF and enrichment of stemness population through the osteopontin/secreted phosphoprotein 1-CD44 axis in PC.

Nallasamy P ，Nimmakayala RK ，Karmakar S ，Leon F ，Seshacharyulu P ，Lakshmanan I ，Rachagani S ，Mallya K ，Zhang C ，Ly QP ，Myers MS ，Josh L ，Grabow CE ，Gautam SK ，Kumar S ，Lele SM ，Jain M ，Batra SK ，Ponnusamy MP ... -  《-》

Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis.

Parte S ，Kaur AB ，Nimmakayala RK ，Ogunleye AO ，Chirravuri R ，Vengoji R ，Leon F ，Nallasamy P ，Rauth S ，Alsafwani ZW ，Lele S ，Cox JL ，Bhat I ，Singh S ，Batra SK ，Ponnusamy MP ... -  《-》

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells.

Barkeer S ，Chugh S ，Karmakar S ，Kaushik G ，Rauth S ，Rachagani S ，Batra SK ，Ponnusamy MP ... -  《BMC CANCER》

Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma.

Nimmakayala RK ，Leon F ，Rachagani S ，Rauth S ，Nallasamy P ，Marimuthu S ，Shailendra GK ，Chhonker YS ，Chugh S ，Chirravuri R ，Gupta R ，Mallya K ，Prajapati DR ，Lele SM ，C Caffrey T ，L Grem J ，Grandgenett PM ，Hollingsworth MA ，Murry DJ ，Batra SK ，Ponnusamy MP ... -  《-》

Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.

Sun L ，Wang Y ，Wang L ，Yao B ，Chen T ，Li Q ，Liu Z ，Liu R ，Niu Y ，Song T ，Liu Q ，Tu K ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》