I actually do a lot of this because I have so many cheap routes to the eastern US and Canada that it really doesn't matter where I fly out of.

I do a bunch of SkyScanner using "United States" or "Canada" as the takeoff location; and then using the airports it gives you first as origin locations in ITA.

So, e.g. let's say I want to go to the UK in November; I just search "United States" to "United Kingdom" in November via SkyScanner, which of course is horribly ambiguous, but it has me choose a destination airport, and I can see that the first five airports (LGW, MAN, EMA, LHR, and GLA) are the cheapest. Selecting each one, I just add any domestic airport I would be willing to fly out of to my origins in ITA: So JFK and EWR to LGW (Megabus $30 RT from Toledo!), + ORD to MAN (5 hour drive), IAD is too expensive to EMA so no IAD, +BOS and LGA to LHR.

If I repeat the above for Canada, I basically find out that YYZ is my only airport out.

So my ITA search becomes:

JFK, EWR, ORD, BOS, YYZ

to

LGW, MAN, EMA, LHR, GLA

for the month of November; which is much, much narrower and reasonable to mess with.

FTR, I booked YYZ to GLA via KEF (6-day stopover!) in November, and I'm freaking excited about it.

You can do the same thing domestically; e.g. fly "United States" to IAD to go to DC (from DTW is basically free).