Dungeons could be replaced with mines, filled with gold/silver/material X. Naturally there would be ancient dragons slumbering under the great mountains of the world, and digging one up could present a problem.
It would actually encourage a lot of the old standbys of D&D. A dungeon crawl, clearing out an old fort, gaurding a caravan from one town to another. The idea that humans would be expanding into areas beyond their immediate control would open up a lot of mercenary work. A boy who was a farmer one day could become a gunslinger the next just by having the guts to strike out on his own.
Steampunk would probably be the way to go. Clockwork crossbows could dish out large numbers of powerful ranged attacks, but take time to reload.
Armor proficiencies could be replaced with dodge bonuses, so fighter typs would still have a combat advantage.
Armor itself should provide some sort of DR, but anything beyond a breast plate would'nt be worthwhile.
Steamworks and alchemy could be the great powers of the new frontier, as those that use such powers are persecuted by the Wizard cast of the old world. This would keep wizards rare, and might make it easier to keep a frontier feel. Clerics would be busy keeping new settlements afloat, and druids would be trying to stop the spread of new settlements. Get arcane magic out of the way for the most part, and the world would have survive on blood, sweat, and tears.