Gene Expression Classifier Reveals Prognostic Osteosarcoma Microenvironment Molecular Subtypes

Abstract

Osteosarcoma (OSA) is the most common bone malignancy and displays high heterogeneity of molecular phenotypes. This study aimed to characterize the molecular features of OSA by developing a classification system based on the gene expression profile of the tumor microenvironment. Integrative analysis was performed using specimens and clinical information for OSA patients from the TARGET program. Using a matrix factorization method, we identified two molecular subtypes significantly associated with prognosis, S1 (infiltration type) and S2 (escape type). Both subtypes displayed unique features of functional significance features and cellular infiltration characteristics. We determined that immune and stromal infiltrates were abundant in subtype S1 compare to that in subtype S2. Furthermore, higher expression of immune checkpoint PDCD1LG2 and HAVCR2 was associated with improved prognosis, while a preferable chemotherapeutic response was associated with FAP-positive fibroblasts in subtype S1. Alternatively, subtype S2 is characterized by a lack of effective cytotoxic responses and loss of major histocompatibility complex class I molecule expression. A gene classifier was ultimately generated to enable OSA classification and the results were confirmed using the GSE21257 validation set. Correlations between the percentage of fibroblasts and/or fibrosis and CD8+ cells, and their clinical responses to chemotherapy were assessed and verified based on 47 OSA primary tumors. This study established a new OSA classification system for stratifying OSA patient risk, thereby further defining the genetic diversity of OSA and allowing for improved efficiency of personalized therapy.

Control of Dendritic Cell Function Within the Tumour Microenvironment

“…CAFs or cancer associated fibroblasts represent a major population in the TME of many solid tumours, however their origin and role in tumour progression is complex and they can generate pro-tumourigenic and anti-tumourigenic secretory factors. Phenotypically and functionally different CAF subtypes based on cell-surface markers such as podoplanin (PDPN), a-smooth muscle actin (aSMA), fibroblastactivated protein (FAP), fibroblast-specific protein-1 (FSP-1/ S100A4), THY1 (also known as CD90), and platelet-derived growth factor receptor-a, and b (PDGFRa and PDGFRb) have been associated with different tumour types, stages and patient survival (107)(108)(109)(110)(111). Recently, the ability of CAFs to modulate the immune responses has been discovered and is being explored to improve cancer therapies.…”

Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness

“…Unlike epithelial cancers, the current understanding of the origin and contribution of CAFs in sarcomas is very limited. Studies in Ewing sarcoma 144 and osteosarcoma 145 have demonstrated that extracellular vesicles and associated cargo secreted from tumor cells drive the transformation of normal fibroblasts into CAFs. On the contrary, rhabdomyosarcoma cells do not rely on CAFs to prime the ECM for local tumor expansion, but rather produce their own ECM with minimal involvement of CAFs 146 .…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Our knowledge remains sparse for other types of solid malignancies of non-epithelial origin, e.g., in sarcomas. Except for Ewing sarcoma [42] and osteosarcoma [43], the role of CAFs in sarcomas of different origins is unclear. Further, CAFs have not been extensively studied in haematological malignancies so far.…”