Thanks Natalie! @cssheehan.bsky.social responsible for all monthy python jokes :)

Looking forward to your feedback as we continue to work this problem!

Super great to work with James LaBelle’s lab on this project! And thanks to everyone involved in the study: Kay Macleod, @cjhphd.bsky.social, Alica Beutel,
@leahziolkowski.bsky.social, Mumina Sadullozoda, @patrickjonker.bsky.social, Darby Agovino, Grace Croley, @guillaumecognet.bsky.social.

(3) Fortress model is insufficient to explain drug resistance in pancreatic. Tolerance (tis but a scratch) also critical to drug resistance. Will need effort on overcoming tolerance in addition to improving drug delivery to improve treatment outcomes.

(2) Simple changes to culture models, like growing cells in the right nutrients, keeps cells in in vivo relevant states that we care about, like being drug resistant. Important for getting models that are predictive for things like drug discovery and for precision medicine.

Implications: (1) Using standard culture models to do things like drug screens, will make apoptosis inducers look great, even though they will have limited efficacy in vivo. Could be fruitful to look at other treatment modalities that kill cells non-apoptotically.

How does the TME/TIFM cause drug resistance? Apoptotic priming gets turn wayyyyy down. So, cells just don’t die from chemo or targeted therapies despite on target action. Call this the “tis but a scratch model” of drug resistance.

Interestingly, we recently made a new cell culture model (TIFM) where PDAC cells are grown in the nutrients they would see IRL (elifesciences.org/articles/81289). TIFM-derived PDAC cell lines maintain the therapy resistant state! So, have a tractable model to study this state now.

Why haven’t we seen this before? Well, if you keep the cancer cells in culture, after a few weeks, the cells become drug sensitive again! So, the tumor imprints a drug-resistant state that cell culture can’t maintain. Critical for chemo and targeted therapy resistance.

So, how else do tumors become drug resistant? @cssheehan.bsky.social cial found even if you take pancreatic cancer cells out of the tumor and look at drug response ex vivo, the cells are drug resistant. Clearly, something else going on beyond the fortress model.

But fortress model can't explain recent findings that tumors are still resistant even if you work to get the drugs in there (pubmed.ncbi.nlm.nih.gov/32030361/) and new mass spec imaging data (pubmed.ncbi.nlm.nih.gov/35005896/) that shows drugs getting into tumors.

Know that pancreatic cancer cells are not inherently drug resistant but that tumors are. What about tumors makes them drug resistant? Longstanding hypothesis is that fibrosis limits drug delivery to tumors making them resistant. We call this the “fortress model”.

Super cool and excited to read!