I'd like to suggest a mainline route, simply because there is a lot more you can do with a longer route. It's a chance to bring more than one operator to a route, not to mention the amount of additional dlc that could be made.
I have a more detailed suggestion of the West Coast Main line here: https://forums.dovetailgames.com/threads/west-coast-main-line.23650/
I was gonna suggest north at first, possibly even starting from Manchester Pic up to Oxenholme and then we could also get the Windermere branch.