Mangini, M. | bioRxiv Science

bioRxiv2022

LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer

Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis. Here, we report a LAMC2-positive cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation, differentiation, and driving metastasis. Mechanistically, mRNA profiling of these cells indicate a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-{beta} signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of transforming growth factor-{beta} (TGF-{beta}) type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated the lung metastasis, primarily originating from LAMC2 expressing cells. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.

cancer biology↗

bioRxiv2022

Profilin 1 deficiency drives mitotic defects and impairs genome stability

Profilin 1 -encoded by PFN1- is a small actin-binding protein with a tumour suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its contribution to tumour development is not fully understood. Using fix and live cell imaging, we report that Profilin 1 inactivation results in multiple mitotic defects, manifested prominently by anaphase bridges, multipolar spindles, misaligned and lagging chromosomes, and cytokinesis failures. Accordingly, next-generation sequencing technologies highlighted that Profilin 1 knock-out cells display extensive copy-number alterations, which are associated with complex genome rearrangements and chromothripsis events in primary pagetic osteosarcomas with Profilin 1 inactivation. Mechanistically, we show that Profilin 1 is recruited to the spindle midzone at anaphase, and its deficiency reduces the supply of actin filaments to the cleavage furrow during cytokinesis. The mitotic defects are also observed in mouse embryonic fibroblasts and mesenchymal cells deriving from a newly generated knock-in mouse model harbouring a Pfn1 loss-of-function mutation. Furthermore, nuclear atypia is also detected in histological sections of mutant femurs. Thus, our results indicate that Profilin 1 has a role in regulating cell division, and its inactivation triggers mitotic defects, one of the major mechanisms through which tumour cells acquire chromosomal instability.

cell biology↗