Thread by @RutterLab

Tonight we have a special installment of #MitoMonday as @ClaireBensard hosts a #Tweetorial on her recent paper in @CellMetabolism #LateNightWithTheRutterLab

Can a specific metabolic program provoke a cell to become a cancer cell? Focusing mainly on glucose, with some thoughts on fatty acids, and glutamine, we tested the uncoupling of glycolysis and glucose oxidation to induce the transformation from stem cell to cancer cell. 2/

Long ago, Otto Warburg observed that cancer cells perform aerobic glycolysis, but we didn’t know how a cell could control flux from cytosolic glycolysis to mitochondrial glucose oxidation until the transporter was identified…bit.ly/2RDELqe #MPC 3/

Glycolysis generates pyruvate which can either become lactate or enter through the Mitochondrial Pyruvate Carrier (MPC) into the mitochondria to fuel the TCA Cycle.
bit.ly/2rtKe8g
bit.ly/33Z80GA
bit.ly/2P39lrz 4/

MPC expression anti-correlates with cancer, particularly in colon cancer (also here bit.ly/2LG2YbD), suggesting cancer cells restrict glucose metabolism to glycolysis through enhanced metabolic compartmentalization and reduced MPC expression. 5/

In many contexts, cancer cells co-opt a normal paradigm. So do stem cells or growing cells require this same compartmentalization? 6/

Stemness and proliferation does not jive with MPC over-expression and glucose oxidation. However, deleting MPC leads to happy stem cells, expanding the proliferating compartment in the crypt. Demonstrated by @JohnSchell: go.nature.com/3596O4W 7/

Similar findings in the skin by @ChristofkLab: go.nature.com/36h7zcb

And in my hands. #repeated #newmousemodel 8/

Quick Aside#1: check out @HansClevers group’s animations!!
1) intestinal crypt normal proliferation : bit.ly/2P6IZFl
2) intestinal tumor initiation : bit.ly/38pgr1m
#scienceanimation #digizyme #coloncrypts #coloncancer 9/

Are these extra dividing cells cancer? No, not at least over the 6 months we tracked MPC deleted mice, indicating that these cells with aberrant metabolism still respond to normal differentiation cues. #healthycolons #negativedata #stillinteresting 10/

If the scales are tipped towards dysplasia with chemical or genetic carcinogenesis, MPC loss led to an increase in the tumors. No increased DNA damage or apoptosis. There are simply more cells proliferating at any given time in the MPC-deleted models. #playingtheodds 11/

Quick aside#2: #notallcancers This might be specific to epithelial cancers or the intestine. Other tissues and stem cells behave differently. Check out some alternate findings:
Hepatocellular Carcinoma: bit.ly/2RApRRB
Prostate Cancer: go.nature.com/3471bmr 12/

MPC over-expression in our fly models blocked hyperproliferation and tumor formation! Curious if one day this could be a cancer prevention target once we know more about how MPC expression is controlled. #futureprojects #MPCforever 13/

So what fuel do you think Stem cells and polyps use to maintain mitochondrial oxidative metabolism if pyruvate is held hostage in the cytosol? 14/

Our approach: freshly isolate intestinal crypts or polyps -> parallel trace using heavy #glucose, #glutamine, and #palmitate. #WhereHasAllThe13Cgone 15/

The #powerhouse keeps on humming without pyruvate. In fact, it didn’t really want to use pyruvate in normal stem cells or MPC-deleted stem cells! And normal stem cells preferred to oxidize lipids anyway! #avocados #passthebutter #BlueOrPurple 16/

In my hands, polyps trended towards using glutamine to generate TCA cycle intermediates, over readily available palmitate and glucose in both MPC-competent and MPC-deleted contexts.

#theGreatGlutamineDebate #exvivotracing #asgoodastherealthing #maybe 17/

Dividing cells in both normal intestinal epithelium and in pre-cancerous polyps have functional mitochondria.

The former prefers fat and the latter may prefer glutamine in our ex vivo set-up.

And deleted MPC further restricts glucose metabolism to glycolysis. 18/

So how does MPC loss increase proliferation or make a cell more likely to transform? 19/

Highly expressed at the top of the crypt, MPC1 and MPC2 are likely components of the differentiated cell’s metabolism. In polyps compared to normal crypts, MPC expression inversely correlates to stem cell markers, particularly the Wnt pathway, eg. Sox9 and Axin2. 20/

To us, this suggests that if a cell is forced to keep a stem cell-like metabolic program, the cell may intrinsically support stem cell signaling in the absence of enhanced extracellular cues. #hypothesis #futuredirections #bigpicture 21/

Final thoughts: nailing down the metabolic contributions to tumor initiation may be a route to cancer prevention. 22/

Caveat: Apply in the context of the healthy tissue’s native metabolism and the link between metabolic perturbations, metabolic compartments, and gene expression.

#MitoMonday #QuestionsWelcome #journalclub #ScienceTwitter #picsbyCanva @canva #LateNightWithTheRutterLab 23/23