# Sponge Morphology of Osteosarcoma Finds Origin in Synergy Between Bone Synthesis and Tumor Growth

## TL;DR

This study reveals how osteosarcoma tumors create a sponge-like bone structure through a synergy between bone formation and tumor growth.

## Contribution

The study identifies a novel synergy between tumor-induced bone synthesis and degradation that shapes osteosarcoma morphology.

## Key findings

- Tumor cells stimulate bone-like material synthesis in the bone marrow, followed by rapid degradation.
- A 3D cellular automaton model accurately reproduces the sponge-like tumor structure observed in mice.
- The synergy between bone synthesis and tumor growth creates a positive feedback loop shaping tumor morphology.

## Abstract

Osteosarcoma is medically defined as a bone-forming tumor with associated bone-degrading activity. There is a lack of knowledge about the network that generates the overproduction of bone. We studied the early stage of osteosarcoma development with mice enduring a periosteum injection of osteosarcoma cells at the proximal third of the tibia. On day 7 (D7), tumor cells activate the over-synthesis of bone-like material inside the medulla. This overproduction of bone is quickly (D13) followed by degradation. Samples were characterized by microfocus small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), optical and electron microscopies, and micro-indentation. This intramedullary apatite–collagen composite synthesis highlights an unknown network of bone synthesis stimulation by extramedullary osteosarcoma cells. This synthesis activation mechanism, coupled with the well-known bone induced osteosarcoma growth activation, produces a rare synergy that may enlighten the final osteosarcoma morphology. With this aim, a 3D cellular automaton was developed that only included two rules. Simulations can accurately reproduce the bi-continuous sponge macroscopic structure that was analyzed from mice tumor micro-tomography. This unknown tumor activation pathway of bone synthesis, combined with the known bone activation of tumor growth, generates a positive feedback synergy explaining the unusual sponge-like morphology of this bone cancer. From a biomaterials point of view, how nature controls self-assembly processes remains an open question. Here, we show how the synergy between two biological growth processes is responsible for the complex morphology of a bone tumor. This highlights how hierarchical morphologies, accurately defined from the nanometer to the centimeter scale, can be controlled by positive feedback between the self-assembly of a scaffold and the deposition of solid material.