(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.

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.

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.

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”.

@cssheehan.bsky.social found most metabolic adaptations could fit into 4 categories (“reduce, reuse,recycle”, “make it yourself”, “never turn down a free lunch” and “become numb”). Good framework for thinking about how cancers adapt to nutrient stress in the microenvironment. 5/6

1. We list all the identified and quantified metabolic stresses that have been observed in PDAC tumors. New tools have provided a lot of insight into these stresses and hope this will be a great resource for folks starting to think about metabolic constraints in this cancer. 3/6

Congrats to Dr. patrickjonker.bsky.social for successfully defending his thesis!

Thus, we thought arginine-stressed PDAC might be sensitive to PUFA. Yep, they are. And mice with arginine-starved pancreas tumors respond to diets that are high in PUFA too. Super excited we found a TME synthetic lethal interaction that we can possibly leverage with dietary interventions 13/17

To learn about the metabolic stress of the TME we measured the levels of nutrients in pancreatic tumors (elifesciences.org/articles/44235 ) and started to grow PDAC cells in Tumor Interstitial Fluid Medium (TIFM) that has nutrient levels of the tumor (elifesciences.org/articles/81289 ). 7/17

Pancreatic tumors have messed up blood vessels and are poorly perfused, which means nutrient delivery is restricted to TME. We posited the metabolic stress could cause synthetic lethal interactions with the cancer cells. 6/17

20 years ago Bill Kaelin posited that in addition to mutations in cancers, the stresses of the #tumormicroenvironment (TME) might also lead to synthetic lethality that could be targeted: pubmed.ncbi.nlm.nih.gov/16110319/. But we have not yet had success targeting the TME 4/17

All cancer therapeutics require therapeutic index, some way of hitting the cancer cells but sparing healthy cells. 2/17

so judgmental