WMG / Ends of the Earth

Marvel Team Up #14 where Spider-Man teamed up with Invincible/Mark Grayson was the very beginning of Dr. Octopus's bodily decay that led up to this point

During that time, Mark showed little control when he tackled Octavius hard and sent him flying across the city with a blow, which even earns him a reprimand from Spider-Man. While Otto's main memories are of Spider-Man and other heroes like Iron Man, Captain America, and Hulk hitting him hard, it was Invincible who truly did the most damage to him and kicked off his bodily decay in this issue since all those other Marvel heroes in the past were presumably operating under general superhero guidelines and hitting Dr. Octopus only hard enough to incapacitate and not necessarily hard enough to kill or maim. However, as Mark had no such restraint at the time, his manhandling of Octavius was the starting point of the supervillain's downward descent and led to Dr. Octopus trying to destroy the entire world and later on, hijacking Peter's body.