Depends on the villain and the story. The Lizard is a logical choice, however the NY clue makes me think it might not be him. At least not as the main villains. Like I said in another thread, I'm thinking right now it's Mysterio with the Lizard possibly playing a role.
If the Lizard is not involved at all, but Mysterio is the villain, I won't be mad. Mysterio is a great villain choice. However, like others have said, if we get Scorpion, Electro, Shocker, Rhino, etc. and no Lizard, then I'll be a bit disappionted.