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

Aug 23, 2021

Contributor: Palanisamy Nallasamy,Rama Krishna Nimmakayala,Saswati Karmakar,Frank Leon,Parthasarathy Seshacharyulu,Imayavaramban Lakshmanan,Satyanarayana Rachagani,Kavita Mallya,Chunmeng Zhang,Quan P Ly,Molly S Myers,Lindenberger Josh,Corinn E Grabow,Shailendra K Gautam,Sushil Kumar,Subodh M Lele,Maneesh Jain,Surinder K Batra,Moorthy P Ponnusamy

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

Tumor-microenvironment (TME) factors and cancer stem cells (CSCs) play a critical role in the aggressiveness of pancreatic cancer (PC). However, the degree to which TME 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 2D and 3D sodium alginate bead-based co-culture models. Immunohistochemistry and immunofluorescence staining were performed for CSCs and fibroblast markers in autochthonous Kras; Trp53; Pdx1-Cre (KPC) mice and human pancreatic tumors. PCR-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 demonstrated 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, CAF co-cultured with PC cells in the 3D model showed a substantial increase in stemness features. CD44 and α-SMA were positively correlated, and their expressions progressively increased from the early to late stages of KPC mice and human pancreatic tumors. OPN/SPP1 was identified as the top-differentially overexpressed gene in CAF-CM-treated PC cells, and knockdown of OPN/SPP1 significantly reduced stemness characteristics in CAF-CM-treated PC cells.
Our data uncover novel insight into the interplay between CAF and enrichment of stemness population through SPP1-CD44 axis in PC.

Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.

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About The Expert

Palanisamy Nallasamy

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Rama Krishna Nimmakayala

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Saswati Karmakar

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Frank Leon

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Parthasarathy Seshacharyulu

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Imayavaramban Lakshmanan

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Satyanarayana Rachagani

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Kavita Mallya

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Chunmeng Zhang

Division of Surgical Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

Quan P Ly

Division of Surgical Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

Molly S Myers

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Lindenberger Josh

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Corinn E Grabow

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Shailendra K Gautam

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Sushil Kumar

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Subodh M Lele

Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Maneesh Jain

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Surinder K Batra

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: sbatra@unmc.edu.

Moorthy P Ponnusamy

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: sbatra@unmc.edu.

References

PubMed